JP5782054B2 - Substituted azabicyclic imidazole derivatives useful as TRPM8 receptor modulators - Google Patents

Description

(Cross-reference of related applications)
This application claims the benefit of US Provisional Application No. 61 / 310,870, filed Mar. 5, 2010. The entire disclosure of the aforementioned related patent application is hereby incorporated by reference for all purposes.

(Field of Invention)
The present invention relates to substituted azabicyclic imidazole derivatives, and pharmaceutical compositions containing them, as well as disorders and conditions regulated by TRPM8 (transient receptor potential, melastatin subfamily, type 8) channels. More specifically for their use in treatment, the compounds of the present invention may be used for inflammatory pain, inflammatory hyperalgesia, inflammatory hypersensitivity conditions, neuropathic pain, neuropathic cold allodynia, inflammatory It is useful in the treatment of somatic hyperalgesia, inflammatory visceral hyperalgesia, cardiovascular disease exacerbated by cold and lung disease exacerbated by cold.

  Transient Receptor Potential (TRP) channels are non-selective cation channels that are activated by various stimuli. Numerous members of the ion channel family, such as the cold menthol receptor, also referred to as TRPM8, have been identified to date (MCKEMY, DD, et al “Identification of a cold receptor for the general role for TRP channels”. in thermosenescence ", Nature, 2002, pp 52-58, vol. 416 (6876)). In general, temperature-sensitive TRP channels and related TRP-like receptors, such as TRPV1 / 2/3 and TRPM8, are associated with certain chemicals that mimic these sensations in addition to threshold temperatures ranging from unpleasant high temperatures to unpleasant low temperatures. It is accompanied by sensory responsiveness to the entire series of thermal exposures that respond selectively to it. In particular, TRPM8 is known to be stimulated by cool to cold temperatures and chemicals such as menthol and icilin, which is responsible for the therapeutic sensation induced by these substances. there is a possibility.

  TRPM8 is located on primary nociceptive neurons (Aδ and C fibers) and is also regulated by second messenger signals mediated by inflammation (ABE, J., et al. “Ca2 + -dependent PKC activation mediasment- Induced desensitization of recipient receptor potential M8, Neurosci. Lett., 2006, pp 140-144, Vol. 397 (1-2); PREMKUMar, L. S., et al. Kinase C-Media ed Dephosphorylation ", J.Neurosci., 2005, pp 11322~11329, Vol.25 (49)). The localization of TRPM8 in both A Aδ and C fibers may provide a basis for abnormal cooling in pathological conditions in which these neurons change and often result in burning-like pain (KOBAYASHI) , K., et al., “Distinction of TRPM8, TRPA1 and TRPV1 mRNAs in rat primary offset neurons with a c-fibers and colcalization. (4), 596-606; ROZA, C. et al., “Cold sensitivity in axomize. fibers of experiential neuromas in mice, Pain, 2006, pp 24-36, Vol 120 (1-2); and XING, H., et al., “Chemical and Cold Sensit of PM Tightly. ", J. Neurophysiol., 2006, pp 1221-1230, Vol. 95 (2)). Cold intolerance and contradictory burn sensations induced by chemical or thermal cooling are very similar to those seen in a wide range of clinical disorders and are therefore novel antisensory hypersensitivity drugs Or provide a strong rationale for the development of TRPM8 modulators as antiallodynia drugs. TRPM8 is also known to be expressed in brain, lung, bladder, gastrointestinal tract, blood vessels, prostate and immune cells, thus providing the potential for therapeutic regulation in a wide range of diseases.

  In the art, chronic or acute pain, or diseases leading to such pain, as well as diseases or conditions, such as pulmonary or vascular dysfunction, are affected by modulation of TRPM8 receptors. There remains a need for TRPM8 antagonists that can be used to treat diseases or conditions.

  The present invention is directed to compounds of formula I, and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof:

Where
R ¹ is selected from the group consisting of hydrogen, fluoro, chloro, fluorinated C _1-4 alkyl and fluorinated C _1-4 alkoxy;
R ² is selected from the group consisting of hydrogen, chloro, bromo, C _1-4 alkyl, fluorinated C _1-4 alkyl and fluorinated C _1-4 alkoxy, provided that R ² is other than hydrogen.

And

Selected from the group consisting of
In the formula, R ³ is hydrogen, chloro, cyano, C _1-4 alkyl, fluorinated C _1-4 alkyl, C _1-4 alkoxy, fluorinated C _1-4 alkoxy, —O— (CH ₂ ) ₂ —. OH, —O—CH ₂ —CO ₂ H, —O— (CH ₂ ) ₂ —O— (C _1-4 alkyl), —O—CH ₂ — (fluorinated C _1-2 alkyl), —O— Selected from the group consisting of (CH ₂ ) ₂ —NR ^A R ^B and —NR ^A R ^B ;
Wherein R ^A and R ^B are each independently selected from the group consisting of hydrogen and C _1-4 alkyl;
Alternatively, R ^A and R ^B together with the nitrogen atom to which they are attached, are pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperidin-1-yl Forming a ring structure selected from the group consisting of 4-methyl-piperazin-1-yl and morpholin-4-yl;
Q is an optionally substituted ring structure selected from the group consisting of rings (a)-(h):

(Optionally substituted 5-pyrazolyl),

(Optionally substituted 4-pyrazolyl)
(Wherein, R ⁵ is C _{1 to 4} alkyl, R ⁶ is selected from the group consisting of C _{1 to 4} alkyl and fluorinated C _{1 to 4} alkyl, R ⁷ is hydrogen, chloro, fluoro, cyano , Selected from the group consisting of C _1-4 alkyl and C _1-4 alkoxy),

(Optionally substituted 2-imidazolyl)
Wherein R ⁸ and R ⁹ are each independently selected from the group consisting of C _1-4 alkyl.

(Optionally substituted 5-isoxazolyl)
Wherein R ¹⁰ is C _1-4 alkyl and R ¹¹ is selected from the group consisting of hydrogen and cyano.

(Optionally substituted 2-thienyl)
Wherein R ¹² and R ¹³ are each independently selected from the group consisting of hydrogen and C _1-4 alkyl.

(Optionally substituted 3-thienyl)
Wherein R ¹⁴ is C _1-4 alkyl.

(Optionally substituted 2-furyl)
In which R ¹⁵ is C _1-4 alkyl and R ¹⁶ is selected from the group consisting of hydrogen, chloro and bromo; and

(Optionally substituted spiro-tricyclic group)
(Wherein R ¹⁷ is C _1-4 alkyl).

  The present invention is further directed to methods for preparing compounds of formula (I). The present invention is further directed to products manufactured according to the processes described herein.

  The present invention is further directed to compounds of formula (IS), and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof:

  The present invention is further directed to a process for the preparation of a compound of formula (IS) or a pharmaceutically acceptable salt thereof. The present invention is further directed to compounds of formula (IS) in crystalline form as described in more detail herein.

  Illustrative of the invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and products manufactured according to the processes described herein. Illustrative of the invention is a pharmaceutical composition made by mixing a product made according to the process described herein with a pharmaceutically acceptable carrier. Illustrative of the invention is a method of making a pharmaceutical composition comprising mixing a product produced according to the process described herein and a pharmaceutically acceptable carrier.

  The present invention is selected from diseases regulated by TRPM8 (inflammatory pain (eg visceral pain)), neuropathic pain (eg neuropathic cold allodynia), cardiovascular disease exacerbated by cold, and lung disease exacerbated by cold A method comprising treating a therapeutically effective amount of any of the above compounds or pharmaceutical compositions to a patient in need of treatment.

  Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament, wherein the medicament is (a) inflammatory pain in a patient in need of treatment, (b) Prepared to treat neuropathic pain, (c) cardiovascular disease exacerbated by cold, or (d) lung disease exacerbated by cold.

Representative pXRD spectrum from a compound of formula (IS) prepared as described in Step H of Example 35.

  The present invention is directed to compounds of formula (I), and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof:

In which R ¹ , R ² ,

And Q are as defined herein. The compounds of the present invention can be administered by inflammatory pain (such as visceral pain), inflammatory hyperalgesia, neuropathic pain (such as neuropathic cold allodynia), inflammatory somatic hyperalgesia, inflammatory visceral hyperalgesia, cold It is useful for the treatment of diseases mediated by TRPM8 such as exacerbated cardiovascular disease and lung disease exacerbated by cold.

  In one embodiment, the present invention is directed to compounds of formula (IA) and pharmaceutically acceptable salts thereof:

In which all variables are as defined herein. In another embodiment, the present invention is directed to compounds of formula (IB) and pharmaceutically acceptable salts thereof:

In which all variables are as defined herein. In another embodiment, the present invention is directed to compounds of formula (IC) and pharmaceutically acceptable salts thereof:

In which all variables are as defined herein. In another embodiment, the present invention is directed to compounds of formula (ID) and pharmaceutically acceptable salts thereof:

In which all variables are as defined herein. In another embodiment, the present invention is directed to compounds of formula (IE) and pharmaceutically acceptable salts thereof:

In which all variables are as defined herein.

  In one embodiment, the present invention is directed to compounds of formula (IS), as well as solvates, hydrates, tautomers or pharmaceutically acceptable salts thereof:

  In another embodiment, the present invention is directed to a compound of formula (IS) or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is directed to a compound of formula (IS) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a sodium salt, potassium salt, hydrochloride salt thereof. , Trifluoroacetate and methanesulfonate, preferably sodium salts thereof.

In one embodiment of the invention, R ¹ is selected from the group consisting of hydrogen, fluoro, chloro, fluorinated C _1-2 alkyl and fluorinated C _1-2 alkoxy. In another embodiment of the invention, R ¹ is selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl and trifluoromethoxy. In another embodiment of the invention, R ¹ is selected from the group consisting of chloro, fluoro, trifluoromethyl and trifluoromethoxy. In another embodiment of the present invention, R ¹ is selected from the group consisting of chloro and trifluoromethyl.

In an embodiment of the invention, R ² is selected from the group consisting of hydrogen, chloro, trifluoromethyl and trifluoromethoxy, provided that R ² is other than hydrogen.

It is. In another embodiment of the invention, R ² is selected from the group consisting of hydrogen and chloro, provided that when R ² is chloro

It is. In another embodiment of the present invention, R ² is hydrogen.

  In one embodiment of the invention,

It is. In another embodiment of the invention,

It is. In another embodiment of the invention,

It is. In another embodiment of the invention,

It is. In another embodiment of the invention,

It is.

  If you are an expert,

It will be understood that in the group definition, the variables X, Y and Z are divalent and are selected to yield the desired ring structure. More specifically, X is selected from the group consisting of CH and N, Y is selected from the group consisting of CH and N, and Z is selected from the group consisting of CH—R ³ and N, where R ³ Is as described herein.

  In one embodiment,

Wherein R ³ is hydrogen, chloro, cyano, C _1-2 alkyl, fluorinated C _1-2 alkyl, C _1-4 alkoxy, fluorinated C _1-2 alkoxy, —O _{- (CH 2) 2 -OH,} -O-CH 2 -CO 2 H, -O- (CH 2) 2 -O- (C 1~4 _{alkyl), - O-CH 2 -} ( fluorinated _{C. 1 to 2} alkyl), —O— (CH ₂ ) ₂ —NR ^A R ^B and —NR ^A R ^B , wherein R ^A and R ^B are each independently hydrogen and C _1-2 alkyl. Or R ^A and R ^B together with the nitrogen atom to which they are attached are pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl- Forms a ring structure selected from the group consisting of piperazin-1-yl and morpholin-4-yl.

  In another embodiment of the invention,

Wherein R ³ is hydrogen, chloro, cyano, C _1-2 alkyl, trifluoromethyl, C _1-4 alkoxy, —O— (CH ₂ ) ₂ —OH, —O—. _{CH 2 -CO 2 H, -O- (} CH 2) 2 -O- (C 1~2 alkyl), O-CH ₂ - (fluorinated C _{1 to 2 alkyl), - O- (CH 2)} 2 - NR ^A R ^B , selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl, wherein R ^A And R ^B are each independently selected from C _1-2 alkyl, or R ^A and R ^B together with the nitrogen atom to which they are attached, pyrrolidin-1-yl, piperidin-1-yl, Piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholine-4- Forming a ring structure selected from the group consisting of yl.

  In another embodiment of the invention,

Selected from the group consisting of

  In another embodiment of the invention,

Selected from the group consisting of In another embodiment of the invention,

Selected from the group consisting of

  In another embodiment of the invention,

Selected from the group consisting of In another embodiment of the invention,

Selected from the group consisting of

In one embodiment of the invention, R ³ is hydrogen, chloro, cyano, C _1-2 alkyl, fluorinated C _1-2 alkyl, C _1-4 alkoxy, fluorinated C _1-2 alkoxy, —O— ( _{CH 2) 2 -OH, -O-} CH 2 -CO 2 H, -O- (CH 2) 2 -O- (C 1~4 _{alkyl), - O-CH 2 -} ( fluorinated C _{1 to 2} alkyl ), —O— (CH ₂ ) ₂ —NR ^A R ^B and —NR ^A R ^B. In another embodiment of the invention, R ³ is hydrogen, chloro, cyano, C _1-2 alkyl, trifluoromethyl, C _1-4 alkoxy, —O— (CH ₂ ) ₂ —OH, —O—CH. _{2 -CO 2 H, -O- (CH} 2) 2 -O- (C 1~2 _{alkyl), - O-CH 2 -} ( fluorinated C _{1 to 2 alkyl), - O- (CH 2)} 2 - NR ^A R ^B , pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl are selected. In another embodiment of the invention, R ³ is hydrogen, chloro, cyano, methyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, isopropoxy, —O— (CH ₂ ) ₂ —OH, —O—. _{CH 2 -CO 2 H, -O- (} CH 2) 2 -OCH 3, -O-CH 2 -CF 3, pyrrolidin-1-yl, piperidin-1-yl, 4-methyl - piperazine-1-yl, _{morpholin-4-yl, -O- (CH 2) 2 -N} (CH 3) 2, -O- (CH 2) 2 - ( _{pyrrolidin-1-yl), - O- (CH 2)} 2 - (4 - methyl - piperazin-1-yl) and -O- (CH _{2) 2} - (selected from the group consisting of morpholin-4-yl).

In another embodiment of the invention, R ³ is hydrogen, chloro, cyano, methyl, trifluoromethyl, trifluoromethoxy, methoxy, isopropoxy, —O— (CH ₂ ) ₂ —OH, —O— (CH _{2) 2 -OCH 3, -O-} CH 2 -CF 3, pyrrolidin-1-yl, piperidin-1-yl, 4-methyl - piperazine-1-yl, morpholin-4-yl, -O- (CH ₂ ) ₂ -N (CH ₃ ) ₂ and -O- (CH ₂ ) _2- (morpholin-4-yl). In another embodiment of the invention, R ³ is hydrogen, chloro, cyano, methyl, trifluoromethyl, trifluoromethoxy, methoxy, isopropoxy, —O— (CH ₂ ) ₂ —OH, —O— (CH _{2) 2 -OCH 3, -O-} CH 2 -CF 3, pyrrolidin-1-yl, piperidin-1-yl, 4-methyl - piperazine-1-yl, morpholin-4-yl and -O- (CH _{2 2} ) Selected from the group consisting of _2- (morpholin-4-yl). In another embodiment of the invention, R ³ is methoxy, isopropoxy, —O— (CH ₂ ) ₂ —OH, —O— (CH ₂ ) ₂ —OCH ₃ , —O—CH ₂ —CF ₃ , piperidin-1-yl, morpholin-4-yl and -O- (CH _{2) 2} - is selected from the group consisting of (morpholin-4-yl). In another embodiment of the present invention, R ³ is selected from the group consisting of chloro, methyl and methoxy.

In one embodiment of the invention, R ^A and R ^B are each independently selected from the group consisting of hydrogen and C _1-2 alkyl, or R ^A and R ^B together with the nitrogen atom to which they are attached. To form a ring structure selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl. In another embodiment of the invention, R ^A and R ^B are each independently selected from C _1-2 alkyl, or R ^A and R ^B are taken together with the nitrogen atom to which they are attached to pyrrolidine. Forms a ring structure selected from the group consisting of -1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl. In another embodiment of the invention, R ^A and R ^B are each ethyl. In another embodiment of the invention, R ^A and R ^B , together with the nitrogen atom to which they are attached, are pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4- Forming a ring structure selected from the group consisting of methyl-piperazin-1-yl and morpholin-4-yl.

  In one embodiment of the invention, Q is one or more ring structures selected from the group consisting of formulas (a)-(h) as defined herein.

  In one embodiment of the invention, Q is

It is. In another embodiment of the invention, Q is

It is.

In one embodiment of the invention, R ⁵ is C _1-4 alkyl. In another embodiment of the present invention, R ⁵ is a C _{1 to 2} alkyl. In another embodiment of the present invention, R ⁵ is selected from the group consisting of tert- butyl and methyl. In another embodiment of the present invention, R ⁵ is methyl.

In one embodiment of the present invention, R ⁶ is selected from the group consisting of C _{1 to 4} alkyl and fluorinated C _{1 to 4} alkyl. In another embodiment of the invention, R ⁶ is selected from the group consisting of tert-butyl, trifluoromethyl and 1,1-dimethyl-2-fluoro-ethyl. In another embodiment of the present invention, R ⁶ is, tert- butyl and 1,1-dimethyl-2-fluoro - is selected from the group consisting of ethyl. In another embodiment of the present invention, R ⁶ is tert- butyl.

In one embodiment of the invention, R ⁷ is selected from the group consisting of hydrogen, chloro, fluoro, cyano, C _1-4 alkyl and C _1-4 alkoxy. In another embodiment of the present invention, R ⁷ is selected from the group consisting of hydrogen, chloro, fluoro, cyano, C _1-2 alkyl and C _1-2 alkoxy. In another embodiment of the present invention, R ⁷ is hydrogen, chloro, fluoro, cyano, selected from the group consisting of methyl and methoxy. In another embodiment of the present invention, R ⁷ is hydrogen, chloro, fluoro, is selected from the group consisting of cyano and methoxy. In another embodiment of the present invention, R ⁷ is selected from the group consisting of chloro and cyano.

  In another embodiment of the invention, Q is

Wherein R ⁸ and R ⁹ are each independently selected from the group consisting of C _1-4 alkyl. In another embodiment of the invention, R ⁸ and R ⁹ are each independently selected from the group consisting of methyl and tert-butyl. In another embodiment of the present invention, R ⁸ is methyl, R ⁹ is tert- butyl.

  In another embodiment of the invention, Q is

Wherein R ¹⁰ is C _1-4 alkyl and R ¹¹ is selected from the group consisting of hydrogen and cyano. In another embodiment of the present invention, R ¹⁰ is C _{1 to 4} alkyl. In another embodiment of the present invention, R ¹⁰ is tert- butyl. In another embodiment of the present invention, R ¹¹ is selected from the group consisting of hydrogen and shear. In another embodiment of the present invention, R ¹¹ is hydrogen.

  In another embodiment of the invention, Q is

Wherein R ¹² and R ¹³ are each independently selected from the group consisting of hydrogen and C _1-4 alkyl. In one embodiment of the invention, R ¹² is hydrogen. In another embodiment of the present invention, R ¹³ is C _{1 to 4} alkyl. In another embodiment of the present invention, R ¹³ is tert- butyl and isopropyl. In another embodiment of the present invention, R ¹³ is isopropyl.

  In another embodiment of the invention, Q is

_Where R ¹⁴ is C _1-4 alkyl. In another embodiment of the present invention, R ¹⁴ is tert- butyl and isopropyl. In another embodiment of the present invention, R ¹⁴ is isopropyl.

  In another embodiment of the invention, Q is

Wherein R ¹⁵ is C _1-4 alkyl and R ¹⁶ is selected from the group consisting of hydrogen, chloro and bromo. In another embodiment of the present invention, R ¹⁵ is C _{1 to 4} alkyl. In another embodiment of the present invention, R ¹⁵ is tert- butyl. In another embodiment of the present invention, R ¹⁶ is selected from the group consisting of hydrogen, chloro and bromo. In another embodiment of the present invention, R ¹⁶ is selected from the group consisting of hydrogen and bromo.

  In another embodiment of the invention, Q is

_Where R ¹⁷ is C _1-4 alkyl. In another embodiment of the present invention, R ¹⁷ is C _{1 to 2} alkyl. In another embodiment of this invention ^R17 is methyl.

  In one embodiment of the invention, Q is an optionally substituted ring structure selected from the group consisting of formulas (a)-(h):

(Wherein, R ⁵ is C _{1 to 4} alkyl, R ⁶ is selected from the group consisting of C _{1 to 4} alkyl and fluorinated C _{1 to 4} alkyl, R ⁷ is hydrogen, chloro, fluoro, cyano , Selected from the group consisting of C _1-2 alkyl and C _1-2 alkoxy),

Wherein R ⁸ and R ⁹ are each independently selected from the group consisting of C _1-4 alkyl.

Wherein R ¹⁰ is C _1-4 alkyl and R ¹¹ is selected from the group consisting of hydrogen and cyano.

Wherein R ¹² and R ¹³ are each independently selected from the group consisting of hydrogen and C _1-4 alkyl.

Wherein R ¹⁴ is selected from the group consisting of C _1-4 alkyl.

In which R ¹⁵ is C _1-4 alkyl and R ¹⁶ is selected from the group consisting of hydrogen, chloro and bromo; and

(Wherein R ¹⁷ is C _1-2 alkyl).

  In another embodiment of the invention, Q is an optionally substituted ring structure selected from the group consisting of formulas (a)-(h):

(Wherein, R ⁵ is C _{1 to 4} alkyl, R ⁶ is selected from the group consisting of C _{1 to 4} alkyl and fluorinated C _{1 to 4} alkyl, R ⁷ is hydrogen, chloro, fluoro, cyano , Selected from the group consisting of C _1-2 alkyl and C _1-2 alkoxy),

Wherein R ⁸ and R ⁹ are each independently selected from the group consisting of C _1-4 alkyl.

Wherein R ¹⁰ is C _1-4 alkyl and R ¹¹ is selected from the group consisting of hydrogen and cyano.

Wherein R ¹² is hydrogen and R ¹³ is selected from the group consisting of C _1-4 alkyl.

Wherein R ¹⁴ is selected from the group consisting of C _1-4 alkyl.

Wherein R ¹⁵ is C _1-4 alkyl and R ¹⁶ is selected from the group consisting of hydrogen and bromo.

(Wherein R ¹⁷ is C _1-2 alkyl).

  In another embodiment of the invention, Q is 1-methyl-3-tert-butyl-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1- Methyl-3-tert-butyl-4-fluoro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazol-5-yl, 1-methyl-3-trifluoromethyl-4- Chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-methoxy-pyrazol-5-yl, 1-methyl-3- (1,1-dimethyl-2-fluoro-ethyl) -4- Chloro-pyrazol-5-yl, 1-tert-butyl-pyrazol-4-yl, 1-tert-butyl-5-methyl-pyrazol-4-yl, 1-methyl-3-tert-butyl-imi Zol-2-yl, 3-tert-butyl-isoxazol-5-yl, 3-tert-butyl-4-cyano-isoxazol-5-yl, 4-isopropyl-thien-2-yl, 5-isopropyl- Thien-3-yl, 4-tert-butyl-fur-2-yl, 4-tert-butyl-5-bromo-fur-2-yl and

Selected from the group consisting of

  In another embodiment of the invention, Q is 1-methyl-3-tert-butyl-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1- Methyl-3-tert-butyl-4-fluoro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazol-5-yl, 1-methyl-3-tert-butyl-4- Methoxy-pyrazol-5-yl, 1-methyl-3- (1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl, 3-tert-butyl-isoxazol-5-yl 3-tert-butyl-4-cyano-isoxazol-5-yl, 4-isopropyl-thien-2-yl, 5-isopropyl-thien-3-yl, 4-tert-butyl-fur 2-yl, 4-tert-butyl-5-bromo - fur-2-yl and

Selected from the group consisting of In another embodiment of the present invention, Q is 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazole-5- Yl, 1-methyl-3- (1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl, 3-tert-butyl-isoxazol-5-yl and

Selected from the group consisting of In another embodiment of the present invention, Q is 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazole-5- Selected from the group consisting of yl and 1-methyl-3- (1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl. In another embodiment of the invention, Q is 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl and 1-methyl-3-tert-butyl-4-cyano-pyrazole-5- Selected from the group consisting of

  In one embodiment, the present invention is directed to compounds of formula (IB), and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof:

Wherein R ¹ , R ² and R ³ are as defined herein.

In one embodiment, the present invention is directed to compounds of formula (IB), wherein R ¹ is from hydrogen, fluoro, chloro, fluorinated C _1-2 alkyl and fluorinated C _1-2 alkoxy. Selected from the group consisting of In another embodiment, the present invention is directed to compounds of formula (IB), wherein R ¹ is selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl and trifluoromethoxy. In another embodiment, the present invention is directed to compounds of formula (IB), wherein R ¹ is selected from the group consisting of chloro, fluoro, trifluoromethyl and trifluoromethoxy. In another embodiment, the present invention is directed to compounds of formula (IB), wherein R ¹ is selected from the group consisting of chloro and trifluoromethyl.

In one embodiment, aimed at compounds of formula (IB), wherein R ² is selected from the group consisting of hydrogen, chloro, trifluoromethyl and trifluoromethoxy. In another embodiment, the present invention is directed to compounds of formula (IB), wherein R ² is selected from the group consisting of hydrogen and chloro. In another embodiment, the present invention is directed to compounds of formula (IB), wherein R ² is hydrogen.

In one embodiment, the present invention is directed to compounds of formula (IB), wherein R ³ is hydrogen, chloro, cyano, C _1-2 alkyl, fluorinated C _1-2 alkyl, C _{1. to 4} alkoxy, fluorinated C _{1 to 2 alkoxy, -O- (CH 2) 2 -OH} , -O-CH 2 -CO 2 H, -O- (CH 2) 2 -O- (C 1~4 alkyl ), —O—CH ₂ — (fluorinated C _1-2 alkyl), —O— (CH ₂ ) ₂ —NR ^A R ^B and —NR ^A R ^B , wherein R ^A and R ^B is independently selected from the group consisting of hydrogen and C _1-2 alkyl, or R ^A and R ^B together with the nitrogen atom to which they are attached, pyrrolidin-1-yl, piperidine- Selected from the group consisting of 1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl Forming a that ring structure. In another embodiment, this invention is directed to compounds of formula (IB), wherein R ³ is hydrogen, chloro, cyano, C _1-4 alkoxy, —O— (CH ₂ ) ₂ —. OH, —O—CH ₂ —CO ₂ H, —O— (CH ₂ ) ₂ —O— (C _1-2 alkyl), —O—CH ₂ — (fluorinated C _1-2 alkyl), —O— (CH ₂ ) ₂ —NR ^A R ^B , pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl Wherein R ^A and R ^B are each independently selected from C _1-2 alkyl, or R ^A and R ^B pyrrolidin-1-yl, piperidin-1-yl, 4-methyl-piperazine-1- Forms a ring structure selected from the group consisting of yl and morpholin-4-yl.

In another embodiment, the present invention is directed to compounds of formula (IB), wherein R ³ is hydrogen, chloro, cyano, methoxy, ethoxy, isopropoxy, —O—CH ₂ —CF _3. , —O— (CH ₂ ) ₂ —OCH ₃ , —O— (CH ₂ ) ₂ —OH, —O— (CH ₂ ) ₂ —CO ₂ H, pyrrolidin-1-yl, morpholin-4-yl, piperidine 1-yl, 4-methyl - Piperiajin-1-yl (4-methyl-piperiazin-1 -yl), - O- (CH 2) 2 -N (CH 3) 2, -O- (CH 2) 2 - (morpholin-4-yl), - from - (piperazin-1-yl 4-methyl -) consisting of the group O-(CH _{2) 2} - (pyrrolidin-l-yl) and -O- (CH _{2) 2} Selected. In another embodiment, the present invention is directed to compounds of formula (IB), wherein R ³ is hydrogen, chloro, cyano, methoxy, isopropoxy, —O—CH ₂ —CF ₃ , — O— (CH ₂ ) ₂ —OCH ₃ , —O— (CH ₂ ) ₂ —OH, pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, 4-methyl-piperazin-1-yl ( 4-methyl-piperiazin-1-yl), —O— (CH ₂ ) ₂ —N (CH ₃ ) ₂ and —O— (CH ₂ ) ₂ — (morpholin-4-yl) . In another embodiment, the present invention is directed to compounds of formula (IB), wherein R ³ is chloro, methoxy, isopropoxy, —O—CH ₂ —CF ₃ , —O— (CH _{2) 2 -OCH 3, -O- (} CH 2) 2 -OH, pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, 4-methyl - Piperiajin-1-yl (4-methyl- piperiazin-1-yl) and —O— (CH ₂ ) ₂ — (morpholin-4-yl). In another embodiment, the present invention is directed to compounds of formula (IB), wherein R ³ is chloro, methoxy, isopropoxy, —O—CH ₂ —CF ₃ , —O— (CH from the group consisting of _{(morpholin-4-yl) - 2) 2 -OCH 3,} -O- (CH 2) 2 -OH, morpholin-4-yl, piperidin-1-yl and -O- (CH _{2) 2} Selected. In another embodiment, the present invention is directed to compounds of formula (IB), wherein R ³ is —OCH ₃ .

  In one embodiment, the present invention is directed to compounds of formula (IB), wherein Q is an optionally substituted ring structure selected from the group consisting of formulas (a)-(h) Is:

(Wherein, R ⁵ is C _{1 to 4} alkyl, R ⁶ is selected from the group consisting of C _{1 to 4} alkyl and fluorinated C _{1 to 4} alkyl, R ⁷ is hydrogen, chloro, fluoro, cyano , Selected from the group consisting of C _1-2 alkyl and C _1-2 alkoxy),

Wherein R ⁸ and R ⁹ are each independently selected from the group consisting of C _1-4 alkyl.

Wherein R ¹⁰ is C _1-4 alkyl and R ¹¹ is selected from the group consisting of hydrogen and cyano.

Wherein R ¹² is hydrogen and R ¹³ is selected from the group consisting of C _1-4 alkyl.

Wherein R ¹⁴ is selected from the group consisting of C _1-4 alkyl.

Wherein R ¹⁵ is C _1-4 alkyl and R ¹⁶ is selected from the group consisting of hydrogen and bromo.

(Wherein R ¹⁷ is C _1-2 alkyl).

  In another embodiment, the present invention is directed to compounds of formula (IB), wherein Q is 1-methyl-3-tert-butyl-pyrazol-5-yl, 1-methyl-3- tert-butyl-4-chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-fluoro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazole- 5-yl, 1-methyl-3-trifluoromethyl-4-chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-methoxy-pyrazol-5-yl, 1-methyl-3- (1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl, 1-tert-butyl-pyrazol-4-yl, 1-tert-butyl-5-methyl-pyrazole-4- Il 1-methyl-3-tert-butyl-imidazol-2-yl, 3-tert-butyl-isoxazol-5-yl, 3-tert-butyl-4-cyano-isoxazol-5-yl, 4-isopropyl- Thien-2-yl, 5-isopropyl-thien-3-yl, 4-tert-butyl-flu-2-yl, 4-tert-butyl-5-bromo-fur-2-yl and

Selected from the group consisting of In another embodiment, the present invention is directed to compounds of formula (IB), wherein Q is 1-methyl-3-tert-butyl-pyrazol-5-yl, 1-methyl-3- tert-butyl-4-chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-fluoro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazole- 5-yl, 1-methyl-3-tert-butyl-4-methoxy-pyrazol-5-yl, 1-methyl-3- (1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazole- 5-yl, 3-tert-butyl-isoxazol-5-yl, 3-tert-butyl-4-cyano-isoxazol-5-yl, 4-isopropyl-thien-2-yl, 5-isopropyl-thi Down-3-yl, 4-tert-butyl - fur-2-yl, 4-tert-butyl-5-bromo - fur-2-yl and

Selected from the group consisting of In another embodiment, the present invention is directed to compounds of formula (IB), wherein Q is 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1- Methyl-3-tert-butyl-4-cyano-pyrazol-5-yl, 1-methyl-3- (1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl, 3- tert-butyl-isoxazol-5-yl and

Selected from the group consisting of In another embodiment, the present invention is directed to compounds of formula (IB), wherein Q is 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1- The group consisting of methyl-3-tert-butyl-4-cyano-pyrazol-5-yl and 1-methyl-3- (1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl Selected from. In another embodiment, the present invention is directed to compounds of formula (IB), wherein Q is 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl and 1- Selected from the group consisting of methyl-3-tert-butyl-4-cyano-pyrazol-5-yl.

Additional embodiments of the present invention may include variables defined herein (ie, R ¹ , R ² ,

Q or the like) is independently any individual substituent or any subset of substituents selected from the complete list as defined herein Includes what is selected.

  Representative compounds of formula (I) are listed in Table 1 below. In another embodiment, the present invention is directed to any single compound or subset of compounds selected from the representative compounds listed in Table 1 below.

  In another embodiment, the invention provides about 10% or more (preferably about 25% or more, more preferably at 0.2 μM) as measured herein according to the procedure described in Biological Example 1 below. Is about 80% or more, more preferably about 80% or more) of the compound of formula (I) that exhibits an inhibition rate (%) of 20% or more at 0.5 μM, more preferably 30 at 1 μM. % Or more is more preferable.

In one embodiment, the present invention provides 0.100 μM or less, preferably about 0.05 μM or less, more preferably about 0.025 μM, as measured herein according to the procedure described in Biological Example 1 below. In the following, it is aimed at compounds of formula (I) which exhibit an IC ₅₀ of more preferably about 0.01 μM or less, more preferably about 0.005 μM or less.

As used herein, the term “alkyl”, whether used alone or as part of a substituent, includes straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like. Unless otherwise indicated, the notation “C X _-Y alkyl” (where X and Y are integers) refers to an alkyl group as defined herein containing X to Y carbon atoms. It shall be shown. For example, the term “C _1-4 alkyl” is intended to include straight and branched alkyl chains containing from 1 to 4 carbon atoms.

As used herein, unless otherwise specified, “alkoxy” shall refer to an oxygen ether radical of the above linear or branched alkyl group. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, tert-butoxy, n-hexyloxy and the like. Similarly, the term "C _{X to Y} alkoxy" (wherein, X and Y are integers) indicates an alkoxy group as defined herein containing an X to Y carbon atoms And For example, the term “C _1-4 alkoxy” is intended to include straight and branched chain alkoxy groups containing 1 to 4 carbon atoms, more specifically methoxy and ethoxy.

As used herein, unless otherwise indicated, the term “fluorinated C _1-4 alkyl” means any C _1-4 alkyl group as defined above substituted with at least one fluorine atom. It shall be. Suitable _{examples, -CF 3, -CH 2 -CF 3} , -CF 2 -CF 2 -CF 2 -CF 3, -CCl 3, CH 2 CCl 3 but are not limited to, those similar thereto, these It is not limited. Similarly, as used herein, unless otherwise indicated, the term “fluorinated C _1-4 alkoxy” is any, substituted with at least one fluorine atom, as defined above. The C _1-4 alkyl group of Suitable _{examples, -OCF 3, -OCH 2 -CF 3} , -OCF 2 -CF 2 -CF 2 -CF 3 but are not limited to, those similar thereto, without limitation.

  When a particular group is “substituted”, the group is independently one or more substituents selected from a list of substituents, preferably 1 to 5 substituents, more preferably 1 to 3 substituents. It may have a substituent, most preferably 1 to 2 substituents.

  In the context of substituents, the term “independently” means that where more than one such substituent is possible, such substituents may be the same or different from each other.

As used herein, the notation “ ^* ” indicates the presence of a stereocenter. If a compound according to the invention has at least one chiral center, it can therefore exist as an enantiomer. If a compound has more than one chiral center, it can exist as a diastereomer. It will be understood that all such isomers and mixtures thereof are embraced within the scope of the invention. Preferably, when the compound is present as an enantiomer, the enantiomer is greater than about 80% or equal to about 80%, more preferably an enantiomeric excess greater than about 90% or equal to about 90%; More preferably, an enantiomeric excess greater than or equal to about 95%, even more preferably an enantiomeric excess greater than or equal to about 98%, most preferably greater than about 99%. Or present with an enantiomeric excess equal to about 99%. Similarly, when the compound is present as a diastereomer, the diastereomer is greater than or equal to about 80% diastereomeric excess, more preferably greater than about 90% or about 90%. Diastereomeric excess equal to, more preferably greater than about 95% or equal to about 95%, even more preferably greater than about 98% or equal to about 98% Present, most preferably at a diastereomeric excess of greater than or equal to about 99%.

  Furthermore, some crystalline forms of the compounds of the invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention can form solvates with water (ie, hydrates) or solvates with common organic solvents, such solvates also It is intended to be included within the scope of the present invention.

Under standard nomenclature used throughout this disclosure, the end of the designated side chain is described first, followed by adjacent functional groups toward the point of attachment. Thus, for example, a “phenyl C ₁ -C ₆ alkylaminocarbonyl C ₁ -C ₆ alkyl” substituent refers to a group of the following formula:

  Abbreviations used in the specification, particularly in the schemes and examples, are as follows:

  As used herein, unless otherwise indicated, the terms “treat”, “treatment” and the like refer to a subject or patient (preferably, for the purpose of addressing a disease, condition, or disorder) Compounds of the present invention for the management and care of mammals, more preferably humans) and for the prevention of the onset of symptoms or complications, the alleviation of symptoms or complications, or the eradication of a disease, condition or disorder Administration.

  As used herein, unless otherwise indicated, the term “prevention” refers to (a) a reduction in the frequency of one or more symptoms, (b) a reduction in the severity of one or more symptoms, (c). It includes delaying or avoiding the onset of additional symptoms, and / or (d) delaying or avoiding the onset of a disorder or condition.

  When the present invention is directed to a prophylactic method, a patient in need of this method (ie, a patient in need of prophylaxis) experiences or exhibits at least one symptom of a disorder, disease or condition to be prevented. Those skilled in the art will appreciate that any patient or affected person (preferably a mammal, more preferably a human) is included. Furthermore, patients in need of this method additionally do not show any symptoms of the disorder, disease or condition to be prevented, but doctors, clinicians are at risk of developing those disorders, disease or condition. Or it may be a patient (preferably a mammal, more preferably a human) that is considered by other medical professionals. For example, as a result of a patient's medical history, including but not limited to a family calendar, individual predisposition, a combined (comorbid) disorder or a combined (complicated) symptom, genetic testing, etc., May be deemed to be at risk (and therefore need to be prevented or prevented).

  The term “subject” as used herein refers to an animal, preferably a mammal, most preferably a human, that is the subject of treatment, observation or experiment. Preferably, the subject has experienced and / or exhibits at least one symptom of the disease or disorder to be treated and / or prevented.

  As used herein, the term “therapeutically effective amount” refers to an alleviation of the symptom of the disease or disorder being treated, as sought by a researcher, veterinarian, physician or other clinician. Means the amount of active compound or pharmaceutical agent that elicits a biological or pharmaceutical response in a tissue system, animal or human being.

  As used herein, the term “composition” refers to a product that contains a particular component in a particular amount, and any product that results directly or indirectly from a combination of a particular component in a particular amount. Intended to include.

  For the purposes of the present invention, the term “antagonist” refers to a compound that can functionally antagonize an ion channel depending on the situation, including but not limited to antagonistic antagonists, non-antagonistic antagonists. , Desensitizing agonists, and partial agonists.

  For purposes of the present invention, the term “modulated by TRPM8” is intended to refer to a pathological condition affected by modulation of TRPM8 channel, including but not limited to a condition mediated by TRPM8 channel. Used.

  A compound of formula (I) is for treating and preventing a disease, syndrome, condition or disorder in a subject such as animals, mammals and humans where the disease, syndrome, pathological condition or disorder is affected by modulation of TRPM8 channel. In this method, it is useful as an antagonist of TRPM8 channel. Such methods administer a therapeutically effective amount of a compound of formula (I), salt, or solvate to subjects including animals, mammals, and humans in need of such treatment or prevention. Including, consisting of, and consisting essentially of. In particular, it is useful for the prevention or treatment of pain or such diseases, syndromes, conditions or disorders that cause pulmonary or vascular dysfunction. More particularly, by administering a compound of formula (I) to a subject in need thereof, the compound of formula (I) is converted into inflammatory pain, inflammatory hypersensitivity state, neuropathic pain, anxiety, It is effective for the prevention or treatment of depression and cardiovascular diseases exacerbated by cold, including peripheral vascular disease, vascular hypertension, pulmonary hypertension, Raynaud's disease, and coronary artery disease.

  Examples of inflammatory pain include inflammatory bowel disease, visceral pain, migraine, postoperative pain, osteoarthritis, rheumatoid arthritis, back pain, low back pain, joint pain, abdominal pain, chest pain, labor pain, musculoskeletal disease, Skin disease, toothache, fever, burns, sunburn, snake bite, poisonous snake bite, spider bite, insect bite, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis / irritability, pruritus, Eczema, sore throat, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, pain syndrome after mastectomy, menstrual pain, endometriosis, headache due to sinusitis, tension headache, or arachnoiditis It is done.

  One type of inflammatory pain is inflammatory hyperalgesia, which is further distinguished as inflammatory body hyperalgesia or inflammatory visceral hyperalgesia. Inflammatory somatic hyperalgesia is characterized by the presence of an inflammatory hyperalgesic state in which hypersensitivity to thermal, mechanical and / or chemical stimuli is observed. Inflammatory visceral hyperalgesia can also be characterized by the presence of an inflammatory hyperalgesic state where strong visceral hypersensitivity exists. Examples of inflammatory hyperalgesia include inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal disease, skin disease, postoperative pain, headache, toothache, burns, sunburn, insect bites, hypersensitive bladder Urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis / irritability, pruritus, eczema, pharyngitis, enteritis, irritable bowel syndrome, Crohn's disease or Pain due to diseases, syndromes, pathological conditions, disorders, or pain conditions, including inflammatory bowel diseases including ulcerative colitis.

  One embodiment of the present invention is directed to a method of treating inflammatory body hyperalgesia in which hypersensitivity to thermal, mechanical and / or chemical stimuli is observed, and to a mammal in need of such treatment. Administering a therapeutically effective amount of a compound, salt or solvate of (I).

  A further embodiment of the present invention is directed to a method of treating inflammatory visceral hyperalgesia in which enhanced visceral excitability is observed, and a therapeutically effective amount of formula (I) for patients in need of such treatment. ) Comprising, or consisting of and / or consisting essentially of administering a compound, salt or solvate of

  A further embodiment of the present invention is directed to a method of treating neuropathic cold allodynia in which hypersensitivity to cold stimuli is observed, and a therapeutically effective amount of a compound of formula (I) for patients in need of such treatment Comprising, or consisting of, administering and / or consisting essentially of administering a salt or solvate.

  Examples of neuropathic pain include cancer, neuropathy, spinal and peripheral nerve surgery, brain tumors, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, neuralgia (e.g., Trigeminal neuralgia, glossopharyngeal neuralgia, postherpetic neuralgia and burning pain), lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathy associated with spinal cord injury, stroke, muscle atrophy Lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatica, glossopharyngeal neuralgia, peripheral neuritis, multiple neuritis, stump pain, phantom limb pain, fracture, oral neuropathic pain, Charcot pain , Complex regional pain syndromes I and II (CRPSI / II), radiculopathy, Guillain-Barre syndrome, sensory abnormal femoral neuralgia, intraoral burning syndrome, optic neuritis, post-fever neuritis, migratory neuritis Segmental neuritis, Gomball neuritis, neuronal injury, cervical neuralgia, cranial neuralgia, knee neuralgia, glossopharyngeal neuralgia, cluster headache, idiopathic neuralgia, intercostal neuralgia, breast neuralgia, Morton neuralgia, nasopharyngeal neuralgia, occipital neuralgia, Pain due to diseases, syndromes, conditions or disorders including erythema, sruder neuralgia, splenopalatin neuralgia, supraorbital neuralgia, vulva pain, or Vidian neuralgia.

  One type of neuropathic pain is neuropathic cold allodynia, which can be characterized by the presence of allodynia associated with neuropathy, where hypersensitivity to cold stimuli is observed. Examples of neuropathic cold allodynia include neuropathic pain (neuralgia), pain caused by surgery or trauma of the spinal cord and peripheral nerves, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, burning pain, Peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex local pain syndromes I and II (CRPSI / II) and diseases, syndromes, pathological conditions including radiculopathy , Allodynia due to disorders, or painful conditions.

  As used herein, unless otherwise noted, the term “cardiovascular disease exacerbated by cold” is intended to include peripheral vascular disease, vascular hypertension, pulmonary hypertension, Raynaud's disease and coronary artery disease.

  In one embodiment, the present invention provides a method of treating inflammatory pain, inflammatory hypersensitivity state or neuropathic pain comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I). With the goal.

  In one embodiment of the invention, the inflammatory pain is inflammatory bowel disease, visceral pain, migraine, postoperative pain, osteoarthritis, rheumatoid arthritis, back pain, low back pain, joint pain, abdominal pain, chest pain, labor pain, Musculoskeletal disease, skin disease, toothache, fever, sunburn, snake bite, poisonous snake bite, spider bite, insect bite, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis / Irritability, pruritus, eczema, sore throat, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, pain syndrome after mastectomy, menstrual pain, endometriosis, headache due to sinusitis, tension headache, Or arachnoiditis. Preferably, the inflammatory pain is inflammatory hyperalgesia.

  In another embodiment of the invention, the inflammatory hyperalgesia is inflammatory body hyperalgesia or inflammatory visceral hyperalgesia.

  In another embodiment, the present invention is directed to a method of treating inflammatory hyperplasia, wherein inflammatory hyperalgesia is inflammation, osteoarthritis, rheumatoid arthritis, low back pain, joint pain, abdominal pain, musculoskeletal system Disease, skin disease, postoperative pain, headache, fibromyalgia, toothache, burns, sunburn, insect bites, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive lung Due to disease, rhinitis, contact dermatitis / irritability, pruritus, eczema, pharyngitis, enteritis, irritable bowel syndrome, Crohn's disease or ulcerative colitis.

  In another embodiment, the present invention is directed to a method of treating an inflammatory hypersensitivity condition, wherein the inflammatory hypersensitivity condition is urinary incontinence, benign prostatic hypertrophy, cough, asthma, rhinitis, nasal hypersensitivity, Itching, contact dermatitis, skin allergies or chronic obstructive pulmonary disease.

  In another embodiment, the present invention is directed to a method of treating neuropathic pain, wherein the neuropathic pain is cancer, neurological disease, spinal cord or peripheral nerve surgery, brain tumor, traumatic brain injury (TBI). ), Spinal cord injury, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, neuralgia, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathy associated with spinal cord injury , Stroke, ALS, Parkinson's disease, multiple sclerosis, sciatica, glossopharyngeal neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, fracture, oral neuropathic pain, Charcot pain, compound Local pain syndromes I and II (CRPSI / II), radiculopathy, Guillain-Barre syndrome, sensory dysfunctional femoral neuralgia, oral burning syndrome, optic neuritis, post-fever neuritis, migratory neuritis, segmental nerve , Gombault neuritis, neuritis, cervical neuralgia, cranial neuralgia, glossopharyngeal neuralgia, cluster headache, idiopathic neuralgia, intercostal brachial neuralgia, breast neuralgia, Morton neuralgia, rhinocephalic neuralgia, occipital neuralgia Due to erythema neuralgia, sluder neuralgia, wing palatal neuralgia, supraorbital neuralgia, vulva pain or paroxysmal neuralgia. Preferably, the neuropathic pain is neuropathic cold allodynia or neuralgia. Preferably, the neuralgia is trigeminal neuralgia, glossopharyngeal neuralgia, postherpetic neuralgia, or burning pain.

  In another embodiment, the present invention is directed to a method of treating neuropathic cold allodynia, wherein the neuropathic cold allodynia is pain caused by surgery or trauma of the spinal cord and peripheral nerves, traumatic brain injury (TBI). ), Trigeminal neuralgia, postherpetic neuralgia, burning pain, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome I and II (CRPSI / II) or It is a radiculopathy.

  In another embodiment, the present invention is directed to a method of treating anxiety, wherein anxiety is social anxiety, post-traumatic stress disorder, phobia, social phobia, specific phobia, panic disorder, obsessive compulsive Disorder, acute stress disorder, separation anxiety disorder or generalized anxiety disorder.

  In another embodiment, the present invention is directed to a method of treating depression, wherein depression is major depression, bipolar disorder, seasonal affective disorder, postpartum depression, manic depression or bipolar depression. I have a disease.

  In another embodiment, the present invention is directed to a method of treating inflammatory body hyperalgesia in which hypersensitivity to thermal stimulation is observed. In another embodiment, the present invention is directed to a method of treating inflammatory visceral hyperalgesia in which increased visceral irritability is observed. In another embodiment, the present invention is directed to a method of treating neuropathic cold allodynia in which hypersensitivity to cold stimuli is observed.

  In another embodiment, the present invention is directed to a method of treating cardiovascular diseases that are exacerbated by cold, such as peripheral vascular disease, vascular hypertension, pulmonary hypertension, Raynaud's disease and coronary artery disease.

  In another embodiment, the invention relates to migraine in mammals, postherpetic neuralgia, posttraumatic neuralgia, postchemotherapy neuralgia, combined regional pain syndromes I and II (CRPS I / II), fibromyalgia, inflammatory bowel Aimed at a method for the treatment and / or prevention of diseases, psychogenic pruritus, asthma, chronic obstructive pulmonary disease, toothache, bone pain or fever, which treats mammals in need of such treatment or prevention Administering a top effective amount of a TRPM8 antagonist.

  In another embodiment, the present invention is directed to a therapeutic and / or prophylactic method, which is directed to a method for treating and / or preventing hypertension, peripheral vascular disease, Raynaud's disease, reperfusion injury or frostbite in a mammal. Administering a therapeutically effective amount of a TRPM8 antagonist to a mammal in need of such treatment or prevention.

  In yet another embodiment, the present invention is directed to a method of promoting waking after anesthesia or recovery after hypothermia in a mammal, wherein the method comprises a therapeutically effective amount for a mammal in need of such treatment. Administration of a TRPM8 antagonist.

  As described in more detail herein, terms such as “reactive” and “reacted” are used herein to refer to (a) the actually described form of such a chemical entity, And (b) refers to the chemical reality that is any one of any form of such chemical entity in the medium in which the compound is considered to be named.

  One skilled in the art will recognize that unless otherwise indicated, the reaction step (s) are performed according to known methods under suitable conditions to provide the desired product. Those skilled in the art will further recognize that, in the specification and claims presented herein, a reagent or reagent class / type (eg, base, solvent, etc.) is cited in more than one step of the process. It will be appreciated that the individual reagents are independently selected for each reaction step and may be the same or different from one another. For example, if the two steps of the method list an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step may be the same or different from the organic or inorganic base of the second step. Good. Furthermore, those skilled in the art will recognize that the reaction steps of the present invention can be performed in a variety of solvents or solvent systems, and that the reaction steps can also be performed in a suitable solvent or mixture of solvent systems. Let's go. One skilled in the art will recognize that the first and second reactions may be performed if two successive reactions or process steps are performed without isolating the intermediate product (ie, the first product of the two successive reactions or process steps). Alternatively, it is further understood that the process steps can be performed in the same solvent or solvent system, or can be performed in a different solvent or solvent system after solvent exchange, which can be completed according to known methods.

  In order to provide a more concise description, some of the quantitative expressions provided for in the present invention are not modified by the term “about”. Whether the term “about” is expressly used or not, any amount provided herein is meant to refer to the actual provided value, and is It is understood that it is also meant to refer to an approximation of such a predetermined value that is reasonably inferred based on those skilled in the art, including an approximation due to experimental and / or measurement conditions for the value.

  In order to provide a more concise description, some of the quantitative expressions herein are described as a range of amounts from about X to about Y. Where a range is described, it is understood that this range is not limited to the upper and lower limits described, but rather includes the entire range of amounts from about X to about Y or any range thereof.

  Examples of suitable solvents, bases, reaction temperatures, and other reaction parameters and components are described in detail herein below. Those skilled in the art will recognize that the listing of the above examples is in no way intended to limit the invention described in the following claims and should not be so construed.

  As used herein, unless otherwise indicated, the term “leaving group” shall mean a charged or uncharged atom or group that leaves during a substitution or alternative reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, triflate and the like.

During any method of preparing the compounds of the invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule involved. This is described in Protective Groups in Organic Chemistry, ed. J. et al. F. W. McOmie, Plenum Press, 1973 and T.W. W. Greene & P. G. M.M. It may be achieved using conventional protecting groups such as those described in Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting group may be removed at a subsequent convenient stage using methods known in the art. As used herein, unless otherwise indicated, the term “nitrogen protecting group” can protect a nitrogen atom from reaction by bonding to the nitrogen atom and can be easily removed after the reaction. It shall mean a group. Suitable nitrogen protecting groups include carbamate groups of formula —C (O) O—R where R is, for example, methyl, ethyl, tert-butyl, benzyl, phenylethyl, CH ₂ ═CH—CH ₂ — And amide groups of formula —C (O) —R ′ where R ′ is, for example, methyl, phenyl, trifluoromethyl and the like, and —SO _2- R "N-sulfonyl derivatives wherein R" is, for example, tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3, 6-trimethyl-4-methoxybenzene and the like), and benzyl groups such as benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl and the like. Without limitation et. Other suitable nitrogen protecting groups, T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, may be found in textbooks such as John Wiley & Sons, 1991.

  If the process for the preparation of the compounds according to the invention yields a mixture of stereoisomers, these isomers can be separated by conventional techniques such as, for example, preparative chromatography. The compounds may be prepared in racemic form or the individual enantiomers can be prepared either by enantioselective synthesis or resolution. The compound is separated after forming a salt using an optically active acid such as (−)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-1-tartaric acid. It can also be resolved into the enantiomers that are components of these compounds by standard techniques such as crystallizing and regenerating the free base to form diastereomeric pairs. The compounds may also be resolved by forming a diastereomeric ester or amide followed by chromatographic separation to remove the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

In addition, enantiomeric excess (% ee) can be determined using chiral HPLC on standards. The enantiomeric excess can be calculated as follows:
[(R mol-S mol) / (R mol + S mol)] × 100%
In the formula, R mole and S mole are R and S mole fractions such that R mole + S mole = 1 in the mixture. Alternatively, the enantiomeric excess can be calculated from the optical rotation of the desired enantiomer and the prepared mixture as follows:
ee = ([α−obs] / [α−max]) × 100.

  One embodiment of the present invention is directed to a composition comprising a dextrorotatory enantiomer of a compound of formula (I), the composition being substantially free of the levorotatory isomer of said compound. “Substantially free” in the context of the present specification means less than 25%, preferably 10%, more preferably 5%, even more preferably less than 2%, and even more preferably the levorotatory isomer determined by the following formula: It means less than 1%.

  Another embodiment of the invention is a composition comprising a levorotatory enantiomer of a compound of formula (I), the composition being substantially free of the dextrorotatory isomer of said compound. In the context of the present specification, “substantially free” means less than 25%, preferably 10%, more preferably 5%, and even more preferably less than 2% of the dextrorotatory isomer as determined by the following formula: Preferably it means less than 1%.

  General synthesis method

Compounds of formula (I) selected from the group consisting of can be prepared as described in Scheme 1 below.

According to this, a suitably substituted compound of formula (IV) which is a known compound or a compound prepared by a known method wherein L ⁰ is suitably selected such as chloro, bromo and the like. And L ¹ is a suitably selected leaving group such as chloro, bromo, triflate and the like) and a suitably selected nucleophile according to known methods Reaction yields the corresponding compound of formula (V).

More specifically, for the preparation of compounds of formula (V) wherein R ³ is —NR ^A R ^B , compounds of formula (IV) are represented by K ₂ CO ₃ , Na ₂ CO ₃ and the like. A compound that is a known compound or a compound prepared by a known method in a suitably selected organic solvent such as DMF, NMP, DMA and the like in the presence of a suitably selected base such as React with a suitably substituted amine of NHR ^A R ^B. For the preparation of compounds of formula (V) where R ³ is cyano, compounds of formula (IV) are prepared in a suitably selected organic solvent such as NMP, DMF and the like, for example NaCN , React with CuCN and the like. R ³ is C _1-4 alkoxy, fluorinated C _1-4 alkoxy, —O— (CH ₂ ) ₂ —OH, —O— (CH ₂ ) ₂ —O— (C _1-4 alkyl), —O—. For the preparation of compounds of formula (V) selected from the group consisting of CH _2- (fluorinated C _1-2 alkyl) and —O— (CH ₂ ) ₂ —NR ^A R ^B Is reacted with the corresponding R ³ —Na or R ³ —K reagent, which is a known compound or a compound prepared by known methods, for example, as will be readily understood by those skilled in the art.

Those skilled in the art, the compound of formula (V) R ³ is _{-O-CH 2 -C (O)} OH is the corresponding formula (V R ³ is -O- (CH _{2) 2} -OH Are further oxidized according to known methods to convert —O—CH ₂ —CH ₂ —OH to the corresponding aldehyde (ie, —O—CH ₂ —CH ₂ —OH to the corresponding —O—CH It will be understood that it can be prepared by conversion to _2- CHO. For example, suitably substituted compounds of formula (V) wherein R ³ is —O— (CH ₂ ) ₂ —OH are such as Dess-Martin periodinane, oxalyl chloride / DMSO and the like according to known methods It can react with suitably selected reagents. The resulting aldehyde compound is then reacted with a suitably selected reagent such as NaClO ₂ and the like in the presence of 2-methyl-2-butene and the like to convert the aldehyde to the corresponding carboxyl. Further oxidation by conversion to an acid (ie, conversion of a —O— (CH ₂ ) ₂ —CHO group to a corresponding —O—CH ₂ —C (O) OH group) yields a compound of formula (V) Can yield compounds.

Compounds of formula (V) wherein R ³ is selected from the group consisting of hydrogen, chloro, C _1-4 alkyl and fluorinated C _1-4 alkyl are known compounds, commercially available compounds or known And is itself selected as a starting material. (Thus, for the above compounds, changes from the compounds of formula (IV) are not essential).

A compound of formula (V) is a suitably substituted compound of formula (VI) which is a known compound or a compound prepared by a known method under suitable coupling conditions, wherein M ¹ is ( a) boronic acid (—B (OH) ₂ ), (b) a suitably selected boron ester such as pinacolatoboryl, neopentylglycolactaboryl and the like, (c) tri (n-butyl) tin and the like A suitably selected trialkylstannyl such as those selected from (d) a triallylsilyl selected suitably such as triallylsilyl and the like, or (e) 2- (hydroxymethyl) phenyl-dimethyl A suitably selected activating group, such as a suitably selected aryldialkylsilyl such as silyl and the like, and the corresponding formula To give a compound of VII).

For example, in the case of a compound of formula (VI) where M ¹ is —B (OH) ₂ or a suitably selected boron ester, the compound of formula (V) is more specifically under Suzuki coupling conditions. , Palladium (II) acetate, palladium (II) chloride, bis (acetonitrile) -dichloro-palladium (II), allyl palladium (II) chloride dimer, tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ ( dba) ₃ ), 2- (di-tert-butylphosphino) biphenyl, dichloro-bis (di-tert-butylphenylphosphine) -palladium (II), (1,1′-bis (di-tert-butylphosphine) Fino) ferrocene) palladium (II) chloride [1,1′-bis- (diphenylphosphino) -ferrocene] -palladium (II) dichloride Chloromethane adduct _{((dppf) PdCl 2 · DCM} ), 2- ( dicyclohexylphosphino) -2 ', 4', 6'-tri - iso - propyl-1,1'-biphenyl, tetrakis (triphenylphosphine) Triphenylphosphine, tri-o-tolylphosphine, tri (tert-butyl) optionally in the presence of a suitably selected palladium catalyst such as palladium (0) (Pd (PPh ₃ ) ₄ ) and the like. ) -Phosphine, tricyclohexylphosphine, 1,1′-bis (diphenylphosphino) -ferrocene, bis [2- (diphenyl-phosphino) phenyl] ether, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, Tris (2-furyl) phosphine, 1-butyl-3-methylimidazolium hex Cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride, potassium fluoride, tetrabutylammonium fluoride, potassium tert-butoxide in the presence of a suitably selected addition ligand such as fluorophosphate and the like Ethanol, THF, DMF, toluene, benzene, DME in the presence of a suitably selected inorganic base such as sodium tert-butoxide, aqueous sodium hydroxide, aqueous sodium bicarbonate, potassium phosphate or preferably aqueous sodium carbonate. In a suitably selected organic solvent or mixture of organic solvents such as 1,4-dioxane and the like, for example in a mixture of toluene and ethanol, preferably in the range of room temperature to about 180 ° C. React with compound of formula (VI) at temperature.

The compound of formula (VII) is in the presence of a suitably selected inorganic base such as sodium hydride, potassium hydride, potassium tert-butoxide, n-butyllithium and the like, preferably sodium hydride. In a suitably selected organic solvent such as DMF, THF and the like, a suitably substituted compound of formula (VIII) which is a known compound or a compound prepared by a known method (wherein , L ³ is a suitably selected leaving group such as chloro, bromo, fluoro and the like, preferably chloro, to give the corresponding compound of formula (IX).

  The compound of formula (IX) can be obtained by using a catalyst such as platinum carbon doped with vanadium, tin (II) chloride, Pt (sulfide) / C and the like in the presence of a catalyst such as palladium carbon and palladium hydrogen. In the presence of a suitably selected organic solvent, such as methanol, ethanol, THF, ethyl acetate and the like, with a suitably selected reducing agent such as hydrogen to give the corresponding formula (X) This yields a compound.

The compound of formula (X) is undiluted or in a suitably selected organic solvent such as 1,4-dioxane, toluene and the like and with POCl ₃ or (1S)-(+)- Reacts with a suitably selected acid catalyst such as 10-camphorsulfonic acid, p-toluenesulfonic acid, acetic acid and the like to give the corresponding compound of formula (Ia).

  Alternatively, the compound of formula (IX) can be prepared neat or in the presence of a suitably selected acid catalyst such as acetic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like, acetic acid, 1,4- A suitably selected such as iron powder and the like, in a suitably selected organic solvent such as dioxane, toluene and the like, preferably at a temperature in the range of about 80 ° C to about 100 ° C. Reacts with a reducing agent to give the corresponding compound of formula (Ia).

The compound of formula (I) is preferably a suitably substituted compound of formula (VII) wherein

And R ³ is hydrogen) with a mixture of SnCl ₂ and hydrochloric acid to reduce the nitro group to the corresponding amino group, while at the same time substituting the R ³ hydrogen group with chloro Prepared by giving the compound of formula (XI).

  The compound of formula (XI) is then reacted with a suitably substituted compound of formula (VIII) as described above to give the corresponding mixture of compounds of formula (XI) and (XII).

  This mixture of compounds is then reacted under ring-closing conditions as described above to yield the corresponding desired compound of formula (I).

Compounds of formula (I) can be prepared according to procedures as described in Scheme 2 below.

According to this, a suitably selected compound of formula (XV) wherein L ¹ is a suitably selected leaving group such as chloro, bromo and the like, preferably bromo, and L ⁴ is a suitably selected leaving group such as chloro, bromo and the like, preferably bromo, and L ¹ and L ⁴ are preferably the same) are sodium hydride, potassium hydride In a suitably selected organic solvent such as DMF, THF and the like in the presence of a suitably selected inorganic base such as potassium tert-butoxide and the like, preferably sodium hydride. A suitably substituted compound of formula (VIII) which is a known compound or a compound prepared by known methods wherein L ³ is chloro, bromo, fluoro and the like Are suitably selected leaving groups such as those, preferably chloro) to give the corresponding compounds of formula (XVI).

The compound of formula (XVI) is optionally in the presence of a base such as TEA, DIPEA and the like, in a suitably selected organic solvent such as THF, DMF, 1,4-dioxane and the like. Preferably in 1,4-dioxane, preferably at temperatures ranging from about room temperature to about 180 ° C., preferably at about 65 ° C., known compounds or compounds prepared by known methods compounds of formula (XVII) which is substituted (wherein, PG ¹ is 4-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, tert- butyl and suitably selected nitrogen protecting group such as those similar thereto And preferably 4-methoxybenzyl-amine to give the corresponding compound of formula (XVIII).

The compound of formula (XVIII) is a suitably substituted compound of formula (VI) under suitable coupling conditions such as described in more detail in Scheme 1 above, wherein M ¹ is (a) Suitably selected boron esters such as boronic acid (—B (OH) ₂ ), (b) pinacolatoboryl, neopentylglycolactoboryl and the like, (c) tri (n-butyl) tin and the like Suitably selected trialkylstannyl such as, (d) suitably selected trialkylsilyl such as triallylsilyl and the like, or (e) 2- (hydroxymethyl) phenyl-dimethylsilyl and A suitably selected activating group, such as a suitably selected aryldialkylsilyl such as the like, and the corresponding To give a compound of (XIX).

The compound of formula (XIX) is deprotected according to known methods to give the corresponding compound of formula (XX). For example, when PG ¹ is 4-methoxybenzyl, the compound of formula (XIX) is undiluted or in a suitably selected organic solvent such as DCE, chloroform and the like, preferably from about room temperature to By deprotection by reaction with a suitably selected acid such as HCl, TFA and the like at a temperature in the range of about 150 ° C., preferably at about 65 ° C., the corresponding formula (XX ).

The compound of formula (XX) is either undiluted or in a suitably selected organic solvent such as 1,4-dioxane, toluene and the like, and POCl ₃ or (1S)-(+)- Reacts with a suitably selected acid catalyst such as 10-camphorsulfonic acid, p-toluenesulfonic acid, acetic acid and the like to give the corresponding compound of formula (Ib).

A compound of formula (I) can alternatively be prepared as described in Scheme 3 below.

According to this, suitably substituted compounds of formula (XXI) which are known compounds or compounds prepared by known methods are sodium hydride, potassium hydride, potassium tert-butoxide, n-butyllithium and these In the presence of a suitably selected base such as those in a suitably selected organic solvent such as THF, DME, DMF, 1,4-dioxane and the like, known compounds or known Reacting with a suitably substituted compound of formula (XXII) which is a compound prepared by the process wherein A ¹ is C _1-4 alkyl or phenyl, preferably methyl or ethyl To yield a compound of formula (XXIII).

  The compound of formula (XXIII) is prepared according to known methods, for example in a suitably selected organic solvent such as toluene, xylene, chlorobenzene and the like, preferably in toluene, at about 80 ° C. to about solvent reflux. Upon heating to a temperature in the temperature range, it is cyclized to give the corresponding compound of formula (XXIV).

  The compound of formula (XXIV) is more suitably selected organic solvents such as acetic acid, sulfuric acid and the like, preferably in acetic acid, preferably at a temperature in the range of about room temperature to about 80 ° C. Reacting with a suitably selected nitrating agent such as nitric acid, fuming nitric acid and the like, preferably at about 60 ° C., yields the corresponding compound of formula (XXV).

The compound of formula (XXV) is undiluted or in a suitably selected organic solvent such as toluene and the like, at a temperature in the range of about 80 ° C. to about 120 ° C., preferably about 100 ° C. Reaction with a suitably selected chlorinating agent such as POCl ₃ , PCl ₃ and the like to yield the corresponding compound of formula (XXVI).

Those skilled in the art will recognize that the compound of formula (XXV) is alternatively POBr ₃ , PBr ₃ and the like in a suitably selected solvent such as undiluted or toluene and the like. Recognizing that it can be reacted with a suitably selected brominating agent such as, to yield the corresponding compound of formula (XXVI), wherein the chloro group at position 4 of the pyridine is substituted with bromo. I will. The compound can then be reacted using bromo rather than chloro as the leaving group, as described herein below.

The compound of formula (XXVI) is suitably selected such as THF, DMF, 1,4-dioxane, ethyl acetate, NMP and the like, optionally in the presence of a base such as TEA, DIPEA and the like. Prepared by known compounds or known methods, preferably in 1,4-dioxane, preferably at temperatures ranging from about room temperature to about 180 ° C., preferably at about 65 ° C. A suitably substituted compound of formula (XVII) wherein PG ¹ is a suitably selected nitrogen protecting group such as tert-butyl, benzyl, 4-methoxybenzyl and the like To give the corresponding compound of formula (XXVII).

One skilled in the art will recognize that the compound of formula (XXVI) is in the range of about 0 ° C. to about 100 ° C. in a suitably selected solvent such as methanol, 1,4-dioxane, NMP, THF and the like. Can react with ammonia or ammonia equivalents such as ammonium acetate and the like at the temperature of to yield the corresponding compound of formula (XXVII), wherein the PG ¹ group is replaced by hydrogen You will recognize that.

For the preparation of compounds of formula (I) wherein R ³ is hydrogen, chloro, C _1-4 alkyl or fluorinated C _1-4 alkyl, compounds of formula (XXVII) wherein R ³ is chloro Is reacted with a suitably selected nucleophile according to known methods to give the corresponding compound of formula (XXIX).

More specifically, the compound of formula (XXIX) wherein R ³ is —NR ^A R ^B in the presence of a suitably selected base such as K ₂ CO ₃ , Na ₂ CO ₃ and the like. A compound of formula (XXVII) in which R ³ is chloro, a known compound or a compound prepared by a known method in a suitably selected organic solvent such as DMF, DMA, NMP and the like Can be prepared by reacting with a suitably substituted amine of the formula NHR ^A R ^B. Further, a compound of formula (XXIX) wherein R ³ is cyano may be a compound of formula (XXVII) wherein R ³ is chloro in a suitably selected organic solvent such as DMF, NMP and the like , NaCN, CuCN and the like can be prepared. Further, R ³ is C _1-4 alkoxy, fluorinated C _1-4 alkoxy, —O— (CH ₂ ) ₂ —OH, —O— (CH ₂ ) ₂ —O— (C _1-4 alkyl), — Compounds of formula (XXIX) selected from the group consisting of O—CH ₂ — (fluorinated C _1-2 alkyl) and —O— (CH ₂ ) ₂ —NR ^A R ^B are readily recognized by those skilled in the art. Thus, a compound of formula (XXVII) can be prepared, for example, by reacting with a corresponding R ³ —Na or R ³ —K reagent that is a known compound or a compound prepared by known methods.

One skilled in the art will recognize that a compound of formula (XXIX) where R ³ is —O—CH ₂ —C (O) OH corresponds to a corresponding formula (XXIX) wherein R ³ is —O— (CH ₂ ) ₂ —OH. Are further oxidized according to known methods to convert —O—CH ₂ —CH ₂ —OH to the corresponding aldehyde (ie, —O—CH ₂ —CH ₂ —OH to the corresponding —O—CH It will be understood that it can be prepared by conversion to _2- CHO. For example, suitably substituted compounds of formula (V) wherein R ³ is —O— (CH ₂ ) ₂ —OH are such as Dess-Martin periodinane, oxalyl chloride / DMSO and the like according to known methods It can react with suitably selected reagents. The resulting aldehyde compound is then reacted with a suitably selected reagent such as NaClO ₂ and the like in the presence of 2-methyl-2-butene and the like to convert the aldehyde to the corresponding carboxyl. Conversion to an acid (ie, conversion of the —O— (CH ₂ ) ₂ —CHO group to the corresponding —O—CH ₂ —C (O) OH group) results in further oxidation to the corresponding formula (XXIX ).

The compound of formula (XXIX) (or when R ³ is hydrogen, the compound of formula (XXVII)) is deprotected according to known methods to give the corresponding compound of formula (XXX). For example, when PG ¹ is p-methoxybenzyl, the compound of formula (XXIX) is preferably diluted from about room temperature to a neat or in a suitably selected organic solvent such as DCE, chloroform and the like. Deprotection by reaction with a suitably selected acid, such as HCl, TFA and the like, at a temperature in the range of about 150 ° C., preferably at about 65 ° C., gives the corresponding formula (XXX ).

The compound of formula (XXX) is prepared in the presence of a suitably selected inorganic base such as sodium hydride, potassium hydride, potassium tert-butoxide and the like, preferably sodium hydride, and DMF, THF and A suitably substituted compound of formula (VIII) which is a known compound or a compound prepared by a known method in a suitably selected organic solvent such as the like, wherein L ³ is chloro Is a suitably selected leaving group such as bromo, fluoro and the like, preferably chloro, to give the corresponding compound of formula (XXXI).

  The compound of formula (XXXI) is a compound of a catalyst such as platinum carbon doped with vanadium, tin (II) chloride, Pt (sulfide) / C and the like in the presence of a catalyst such as palladium carbon and palladium hydrogen. Reacts with a suitably selected reducing agent such as hydrogen in a suitably selected organic solvent such as methanol, ethanol, THF and the like in the presence to give the corresponding compound of formula (XXXII) .

The compound of formula (XXXII) can be used undiluted or in a suitably selected organic solvent such as 1,4-dioxane, toluene and the like and with POCl ₃ or (1S)-(+)- Reacts with a suitably selected acid catalyst such as 10-camphorsulfonic acid, p-toluenesulfonic acid, acetic acid and the like to give the corresponding compound of formula (Ic).

  Alternatively, the compound of formula (XXXI) can be prepared neat or in the presence of a suitably selected acid catalyst such as acetic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like, acetic acid, 1,4- A suitably selected such as iron powder and the like, in a suitably selected organic solvent such as dioxane, toluene and the like, preferably at a temperature in the range of about 80 ° C to about 100 ° C. Reacts with a reducing agent to give the corresponding compound of formula (Ic).

A compound of formula (I) can be prepared as described in Scheme 4 below.

According to this, a suitably substituted compound of formula (XXXIII) which is a known compound or a compound prepared by a known method wherein L ⁵ is chloro, bromo, triflate and the like A suitably selected leaving group is a suitably substituted compound of formula (VI) which is a known compound or a compound prepared by a known method under suitable coupling conditions, wherein M ¹ is a suitably selected boron ester such as (a) boronic acid (—B (OH) ₂ ), (b) pinacolatoboryl, neopentylglycolactoboryl and the like, (c) tri (n— (B) suitably selected trialkylstannyl such as tin and the like, (d) suitably selected trialkylsilyl such as triallylsilyl and the like Or (e) a suitably selected activating group, such as a suitably selected aryldialkylsilyl such as 2- (hydroxymethyl) phenyl-dimethylsilyl and the like). To give the corresponding compound of formula (XXXIV).

For example, in the case of a compound of formula (VI) where M ¹ is —B (OH) ₂ or a suitably selected boron ester, the compound of formula (XXXIII), more specifically, under Suzuki coupling conditions , Palladium (II) acetate, palladium (II) chloride, bis (acetonitrile) -dichloro-palladium (II), allyl palladium (II) chloride dimer, tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ ( dba) ₃ ), 2- (di-tert-butylphosphino) biphenyl, dichloro-bis (di-tert-butylphenylphosphine) -palladium (II), [1,1′-bis- (diphenylphosphino)- Ferrocene] -palladium (II) dichloride dichloromethane adduct ((dppf) PdCl ₂ · DCM), 2- (dicyclohexyl) Phosphino) -2 ′, 4 ′, 6′-tri-i-propyl-1,1′-biphenyl, tetrakis (triphenylphosphine) palladium (0) (Pd (PPh ₃ ) ₄ ), 1,1′-bis In the presence of a suitably selected palladium catalyst such as (di-tert-butylphosphino) ferrocene palladium (II) and the like, optionally triphenylphosphine, tri-o-tolylphosphine, tri (tert -Butyl) -phosphine, tricyclohexylphosphine, 1,1'-bis (diphenylphosphino) -ferrocene, bis [2- (diphenyl-phosphino) phenyl] ether, 2-dicyclohexylphosphino-2 ', 6'-dimethoxy Biphenyl, tris (2-furyl) phosphine, 1-butyl-3-methylimidazolium hexa Cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride, potassium fluoride, tetrabutylammonium fluoride, potassium tert- in the presence of a suitably selected addition ligand such as urophosphate and the like Ethanol, THF, DMF, toluene, benzene, in the presence of a suitably selected inorganic base such as butoxide, sodium tert-butoxide, aqueous sodium hydroxide, aqueous sodium bicarbonate, potassium phosphate or preferably aqueous sodium carbonate, Reacting with a compound of formula (VI) in a suitably selected organic solvent such as DME, 1,4-dioxane and the like, preferably at a suitable temperature ranging from room temperature to about 180 ° C.

The compound of formula (XXXIV) is in the presence of a suitably selected inorganic base such as sodium hydride, potassium hydride, potassium tert-butoxide, n-butyllithium and the like, preferably sodium hydride. In a suitably selected organic solvent such as DMF, THF and the like, a suitably substituted compound of formula (VIII) which is a known compound or a compound prepared by a known method (wherein , L ³ is a suitably selected leaving group such as chloro, bromo, fluoro and the like, preferably chloro, to give the corresponding compound of formula (XXXV).

  The compound of formula (XXXV) is a compound of a catalyst such as platinum carbon doped with vanadium, tin (II) chloride, Pt (sulfide) / C and the like in the presence of a catalyst such as palladium carbon or palladium hydrogen. Reacts with a suitably selected reducing agent such as hydrogen in a suitably selected organic solvent such as methanol, ethanol, THF and the like in the presence to give the corresponding compound of formula (XXXVI) .

The compound of formula (XXXVI) can be used undiluted or in a suitably selected organic solvent such as 1,4-dioxane, toluene and the like with POCl ₃ or (1S)-(+)- Reacts with a suitably selected acid catalyst such as 10-camphorsulfonic acid, p-toluenesulfonic acid, acetic acid and the like to give the corresponding compound of formula (Id).

  Alternatively, the compound of formula (XXXV) can be prepared neat or in the presence of a suitably selected acid catalyst such as acetic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like, acetic acid, 1,4- A suitably selected such as iron powder and the like, in a suitably selected organic solvent such as dioxane, toluene and the like, preferably at a temperature in the range of about 80 ° C to about 100 ° C. Reacts with a reducing agent to give the corresponding compound of formula (Id).

A compound of formula (I) can be prepared according to the process outlined in Scheme 5 below.

According to this, a suitably substituted compound of formula (XL) which is a known compound or a compound prepared by a known method wherein L ⁴ is suitably selected such as chloro, bromo and the like Wherein E ¹ is selected from the group consisting of hydrogen, chloro, C _1-4 alkyl and fluorinated C _1-4 alkyl) is suitably substituted under suitable coupling conditions A compound of formula (VI) wherein M ¹ is suitably selected such as (a) boronic acid (—B (OH) ₂ ), (b) pinacolatoboryl, neopentylglycolactaboryl and the like Preferably selected trialkylstannyl such as (c) tri (n-butyl) tin and the like, (d) triallylsilyl and the like G Or (e) a suitably selected activating group such as (e) a suitably selected aryldialkylsilyl such as 2- (hydroxymethyl) phenyl-dimethylsilyl and the like). To yield the corresponding compound of formula (XLI).

For example, in the case of a compound of formula (VI) where M ¹ is —B (OH) ₂ or a suitably selected boron ester, the compound of formula (XL) is more specifically under Suzuki coupling conditions. , Palladium (II) acetate, palladium (II) chloride, bis (acetonitrile) -dichloro-palladium (II), allyl palladium (II) chloride dimer, tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ ( dba) ₃ ), 2- (di-tert-butylphosphino) biphenyl, dichloro-bis (di-tert-butylphenylphosphine) -palladium (II), [1,1′-bis- (diphenylphosphino)- Ferrocene] -palladium (II) dichloride dichloromethane adduct ((dppf) PdCl ₂ · DCM), 2- (dicyclohexylphosphite) F) -2 ′, 4 ′, 6′-tri-iso-propyl-1,1′-biphenyl, tetrakis (triphenylphosphine) palladium (0) (Pd (PPh ₃ ) ₄ ), 1,1′-bis In the presence of a suitably selected palladium catalyst such as (di-tert-butylphosphino) ferrocene palladium (II) and the like, optionally triphenylphosphine, tri-o-tolylphosphine, tri (tert -Butyl) -phosphine, tricyclohexylphosphine, 1,1'-bis (diphenylphosphino) -ferrocene, bis [2- (diphenyl-phosphino) phenyl] ether, 2-dicyclohexylphosphino-2 ', 6'-dimethoxy Biphenyl, tris (2-furyl) phosphine, 1-butyl-3-methylimidazolium hexafluo In the presence of a suitably selected addition ligand such as phosphate and the like, cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride, potassium fluoride, tetrabutylammonium fluoride, potassium tert-butoxide, In the presence of a suitably selected inorganic base such as sodium tert-butoxide, aqueous sodium hydroxide, aqueous sodium bicarbonate, potassium phosphate or preferably aqueous sodium carbonate, ethanol, THF, DMF, toluene, benzene, DME, Reaction with a compound of formula (VI) in a suitably selected organic solvent such as 1,4-dioxane and the like, preferably at a suitable temperature ranging from room temperature to about 180 ° C.

The compound of formula (XLI) reacts with a suitably selected nitrating agent such as nitric acid, potassium nitrate and the like in a suitably selected organic solvent such as concentrated sulfuric acid and the like, (Wherein R ³ is a corresponding E ¹ substituent selected from the group consisting of hydrogen, chloro, C _1-4 alkyl and fluorinated C _1-4 alkyl) . One of ordinary skill in the art can react a compound of formula (XLI) by reacting with other known nitrating agents according to known methods (eg, by reacting with nitronium tetrafluoroborate in DCM). This can yield the compound of (XLIII).

Alternatively, in the case of a compound of formula (XLI) where E ¹ is chloro, the compound of formula (XLI) is nitric acid, potassium nitrate and the like in a suitably selected organic solvent such as concentrated sulfuric acid and the like. Reaction with a suitably selected nitrating agent such as the like may yield the corresponding compound of formula (XLII).

The compound of formula (XLII) is then reacted according to known methods with a suitably selected nucleophile to give the corresponding compound of formula (XLIII) wherein R ³ is —NR ^A R ^B , Cyano, C _1-4 alkoxy, fluorinated C _1-4 alkoxy, —O— (CH ₂ ) ₂ —OH, —O— (CH ₂ ) ₂ —O— (C _1-4 alkyl), —O— CH ₂ — (fluorinated C _1-2 alkyl) and —O— (CH ₂ ) ₂ —NR ^A R ^B are corresponding substituents selected from the group consisting of:

More specifically, for the preparation of compounds of formula (XLV) wherein R ³ is —NR ^A R ^B , compounds of formula (XLII) are represented by K ₂ CO ₃ , Na ₂ CO ₃ and the like. Formulas that are known compounds or compounds prepared by known methods in suitably selected organic solvents such as DMF, DMA, NMP and the like in the presence of a suitably selected base such as React with a suitably substituted amine of NHR ^A R ^B. For the preparation of compounds of formula (XLIII) where R ³ is cyano, compounds of formula (XLII) are prepared in a suitably selected organic solvent such as DMF, NMP and the like, for example NaCN , React with CuCN and the like. R ³ is C _1-4 alkoxy, fluorinated C _1-4 alkoxy, —O— (CH ₂ ) ₂ —OH, —O— (CH ₂ ) ₂ —O— (C _1-4 alkyl), —O—. For the preparation of compounds of formula (XLIII) selected from the group consisting of CH _2- (fluorinated C _1-2 alkyl) and —O— (CH ₂ ) ₂ —NR ^A R ^B Is reacted with the corresponding R ³ —Na or R ³ —K reagent, which is a known compound or a compound prepared by known methods, for example, as will be readily understood by those skilled in the art.

One skilled in the art will recognize that a compound of formula (XLV) where R ³ is —O—CH ₂ —C (O) OH corresponds to a corresponding formula (XLV) wherein R ³ is —O— (CH ₂ ) ₂ —OH. Are further oxidized according to known methods to convert —O—CH ₂ —CH ₂ —OH to the corresponding aldehyde (ie, —O—CH ₂ —CH ₂ —OH to the corresponding —O—CH It will be understood that it can be prepared by conversion to _2- CHO. For example, a suitably substituted compound of formula (XLV) wherein R ³ is —O— (CH ₂ ) ₂ —OH is such as Dess-Martin periodinane, oxalyl chloride / DMSO and the like according to known methods It can react with suitably selected reagents. The resulting aldehyde compound is then reacted with a suitably selected reagent such as NaClO ₂ and the like in the presence of 2-methyl-2-butene and the like to convert the aldehyde to the corresponding carboxyl. Further oxidation by conversion to an acid (ie, conversion of a —O— (CH ₂ ) ₂ —CHO group to a corresponding —O—CH ₂ —C (O) OH group) yields a compound of formula (XLV) Can yield compounds.

  The compound of formula (XLIII) is then further reacted as described herein to give the corresponding compound of formula (Ie). More specifically, the compound of formula (XLIII) is used in place of the compound of formula (VII) and reacts as described in Scheme 1 above to give the corresponding compound of formula (Ie). (More specifically, a compound of formula (XLIII) is reacted with a suitably selected compound of formula (VIII) and then further reacted according to the above one-step or two-step process to convert the nitro group to the corresponding amine. And ring closure yields the corresponding compound of formula (Ie).)

  For use in medicine, the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts." However, other salts may be useful in the preparation of the compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compound include, for example, a solution of the compound in a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid. Or the acid addition salt which can be mixed and mixed with the solution of phosphoric acid is mentioned. Further, when the compound of the present invention has an acidic moiety, suitable pharmaceutically acceptable salts thereof include alkali metal salts (for example, sodium salt or potassium salt), alkaline earth metal salts (for example, calcium salt or magnesium). Salts), and salts formed with suitable organic ligands (eg, quaternary ammonium salts, etc.). Thus, representative pharmaceutically acceptable include, but are not limited to: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate , Bromide, calcium edetate, esultin, cansylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edicylate, estratate, esylate, fumarate , Glyceptate, Gluconate, Glutamate, Glycolylarsanilate, Hexyl Resorcinate, Hydlabamine, Hydrobromide, Hydrochloride, Hydroxynaphthalate, Iodide, Isothionate, Lactate, Lactobionic acid Salt, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, Mucoate, napsilate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylic acid Salts, stearate, sulfate, basic acetate, succinate, tannate, tartrate, theocrate, tosylate, triethiodide and valerate.

  Representative acids that can be used to prepare pharmaceutically acceptable salts include, but are not limited to: acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbine Acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S) -camphor-10-sulfonic acid, capric acid, capron Acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, Glucoheptonic acid, D-gluconic acid, D-glucaronic acid, L-glutamic acid, α-oxo-glutaric acid, glucose Cholic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±) -DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic Acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfone Acid and undecylenic acid.

  Representative bases that can be used in the preparation of pharmaceutically acceptable salts include, but are not limited to: ammonia, L-arginine, venetamine, benzathine, calcium hydroxide, choline, deanol. , Diethanolamine, diethylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4- (2-hydroxyethyl) -morpholine, piperazine Potassium hydroxide, 1- (2-hydroxyethyl) -pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide.

  The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs are functional derivatives of the compounds that can be readily converted into the required compounds in vivo. That is, in the treatment methods of the present invention, the term “administration” refers to the various disorders described, with or without the disclosure of specifically disclosed compounds, but after being administered to a patient. Treatment with compounds that convert to a particular compound in vivo should be included. General procedures for selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

  The present invention further comprises a pharmaceutical composition comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier. A pharmaceutical composition containing one or more of the compounds of the invention described herein as an active ingredient is obtained by intimately mixing the compound or compound with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Can be prepared. The carrier may take a wide variety of forms depending on the desired route of administration (eg, oral, parenteral). Thus, for oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, colorants and the like. In oral solid preparations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like. Oral solid preparations may be coated with substances such as sugars or enteric coated to adjust the primary absorption site. Carriers for parenteral administration usually consist of sterile water, and other ingredients may be added to improve solubility or storage. Injectable suspensions or solutions may be prepared using aqueous carriers along with appropriate additives.

  In order to prepare a pharmaceutical composition of the invention, one or more compounds of the invention as an active ingredient are intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, Various forms can be taken depending on the form of the formulation desired for parenteral administration, eg, oral or intramuscular. Any conventional pharmaceutical vehicle can be used to prepare the composition in an oral dosage form. Thus, for example, suitable carriers and additives for oral liquid preparations such as suspensions, elixirs and solutions include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like, Suitable carriers and additives for oral solid preparations such as powders, capsules, caplets, gel cups and tablets include starches, sugars, diluents, granulating agents, lubricants, binders, tablet disintegrating agents and Includes similar items. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. Parenteral carriers usually contain sterile water, but may contain other ingredients for purposes such as to aid solubility or for storage. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be used. The pharmaceutical compositions herein will contain the active ingredient in an amount necessary to deliver an effective dose as described above per unit dose, eg, tablets, capsules, powders, injections, teaspoon and the like. Let's go. The pharmaceutical composition herein is about 0.01 to about 1000 mg per dosage unit (e.g., tablets, capsules, powders, injections, suppositories, teaspoon and the like) or any amount or range therein About 0.01 mg / kg / day to about 300 mg / kg / day or any amount or range therein, preferably about 0.1 to about 50 mg / kg / day or any amount therein or Dosage in a range, more preferably about 0.1 to about 10 mg / kg / day or any amount or range therein, preferably about 0.1 to about 5 mg / kg / day or any amount or range therein May be given in quantity. However, the dosage may vary depending on the patient's requirements, the severity of the condition being treated, and the compound used. Either daily administration or subsequent cyclic administration can be used.

  Preferably, these compositions are for oral, parenteral, intranasal, sublingual or rectal administration, or administration by inhalation or insufflation, eg tablets, pills, capsules, powders, granules, sterile parenteral It is in unit dosage form such as solution or suspension, metered aerosol or liquid propellant, drop, ampoule, autoinjector or suppository. Alternatively, the composition can be present in a form suitable for once-weekly or monthly administration, eg, an insoluble salt of the active compound, such as a decanoate salt, for a depot for intramuscular injection. Can be adapted to provide. For the preparation of solid compositions such as tablets, the principal active ingredient is a pharmaceutical carrier, such as a conventional tablet forming ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, diphosphate. Mix with calcium or gum and other pharmaceutical diluents such as water to form a solid pre-blended composition containing a homogeneous mixture of a compound of the invention or a pharmaceutically acceptable salt thereof. When these pre-blended compositions are referred to as homogeneous, this is a dosage form such as tablets, pills and capsules in which the active ingredient is evenly distributed throughout the composition and thus the composition is equally effective. It can be easily divided into This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.01 to about 1000 mg (or any amount or range therein) of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise formulated to provide a dosage form that provides long-acting benefits. For example, the tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being in the form of the former skin. The two components can be separated by an enteric layer that prevents disintegration in the stomach and allows the internal components to pass intact into the duodenum or to be delayed in release. Various materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

  Liquid forms that may incorporate the novel compositions of the invention for oral or infusion administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and cottonseed oil, sesame oil, coconut oil or peanuts Flavored emulsions with edible oils such as oils, and elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

  The treatment of disorders mediated by TRP M8 according to the present invention can also be performed using a pharmaceutical composition comprising any compound as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may comprise from about 0.01 mg to about 1000 mg of compound, or any value or range in this range, preferably from about 0.1 mg to about 500 mg of compound, or any value in this range or A range may be included and further included in any form suitable for the selected method of administration. Carriers include necessary and inert pharmaceutical excipients, including but not limited to binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (including rapid release, timed release and sustained release formulations, respectively), granules, and powders as well as solutions, syrups Liquid forms such as emulsions and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

  Advantageously, the compounds of the invention may be administered in a single daily dose, or the total daily dose may be administered in two, three or four divided doses per day. In addition, the compounds for the present invention may be administered in an intranasal dosage form by topical use of a suitable intranasal vehicle or via a transdermal skin patch, well known to those skilled in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

  For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with a non-toxic, pharmaceutically acceptable oral inert carrier such as ethanol, glycerol, water and the like. In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, benzoic acid Examples include, but are not limited to sodium, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to starch, methylcellulose, agar, bentonite, xanthan gum and the like.

  The liquid takes the form of suitably flavored suspending or dispersing agents such as synthetic and natural rubbers such as tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

  To prepare the pharmaceutical compositions of the invention, the compound of formula (I) as the active ingredient is intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, but the carrier is administered (eg, Depending on the form of the formulation desired (orally or parenterally). Suitable pharmaceutically acceptable carriers are well known in the art. Some descriptions of the pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

  Methods for formulating pharmaceutical compositions are described, for example, in Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, Lieberman et al ed. , Pharmaceutical Dosage Forms: Parental Medicines, Volumes 1-2, Avis et al. ed. And Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, Lieberman et al. ed. (Marcel Dekker, Inc.) and many other publications.

  The compounds of the present invention can be administered in any of the foregoing compositions and in accordance with established dosage regimens whenever it is necessary to treat a disorder mediated by TRP M8.

  The daily dose of the product can vary from 0.01 to about 1,000 mg per day for a human adult or a wide range of any value or range in this range. For oral administration, the composition is preferably 0.01, 0.05, 0.1, 0.5, 1.0, 2.5 for symptomatic adjustment of the dose to the patient to be treated. , 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 milligrams of the active ingredient are preferably provided. An effective amount of the drug is usually provided at a dosage level of about 0.01 mg / kg to about 300 mg / kg body weight per day, or any value or range in this range. Preferably, this range is from about 0.1 mg / kg body weight to about 50.0 mg / kg body weight per day, or any amount or range therein. More preferably, this range is from about 0.1 mg / kg / day to about 10 mg / kg / day, or any amount or range therein. More preferably, this range is from about 0.1 mg / kg / day to about 5 mg / kg / day, or any amount or range therein. In one embodiment, the range is from about 0.5 to about 10 mg / kg body weight per day, or any range therein. The compounds may be administered on a regimen of 1 to 4 times per day.

  The optimal dosage to be administered can be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the formulation, the mode of administration, and the progression of the disease state. In addition, factors associated with the particular patient being treated, such as patient age, weight, diet and time of administration, may also be required in adjusting the dose.

  One skilled in the art will recognize that both in vivo and in vitro testing using known and generally accepted suitable cells and / or animal models can predict the ability of a test compound to treat or prevent a given disease. Will. The skilled artisan further conducts human clinical trials, including first-in-human, dose ranges and efficacy studies, in healthy subjects and / or patients suffering from the above disorders. It will be appreciated that it can be performed according to methods well known in the medical field.

  The following examples are presented to aid the understanding of the present invention and are not intended and should not be construed as limiting in any way the present invention as set forth in the claims that follow. Absent.

  In the following examples, some synthesis products are listed as isolated as a residue. One skilled in the art will recognize that the term “residue” is not limited to the physical state in which the product is isolated, but may include, for example, solids, oils, foams, gums, syrups, and the like. You will understand.

  Examples AO which follow herein below describe the synthesis of intermediates in the synthesis of compounds of formula (I).

(Example A)
5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid

Step A: 5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester Ethyl 5,5-dimethyl-2,4-dioxo-hexanoate (1.02 g, 5.09 mmol) was added to absolute EtOH ( 20 mL). CH ₃ NHNH ₂ (0.270 mL, 5.09 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was warmed to 80 ° C. over 4 hours and then cooled to room temperature. The solvent was removed under reduced pressure and the resulting residue was chromatographed using a 70 g pre-packed SiO ₂ column eluting with 1:19 EtOAc-hexane to give the title compound as a colorless oil. occured. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.68 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.12 (s, 3H), 1.38 (t , J = 7.1 Hz, 3H), 1.30 (s, 9H).

Step B: 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.08 g, 5.14 mmol, (Prepared as described in previous step) was dissolved in MeOH (15 mL) and H ₂ O (15 mL) and 2.5 M aqueous NaOH (5.00 mL, 12.5 mmol) were added. The resulting mixture was stirred at room temperature for 72 hours and then extracted with Et ₂ O (2 × 10 mL). The aqueous layer was acidified with 3M aqueous HCl to about pH 2 and the product was extracted with DCM (3 × 20 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered and the solvent removed under reduced pressure to yield the title compound as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.80 (s, 1H), 4.15 (s, 3H), 1.32 (s, 9H).

(Example B)
Step B: 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid

Step A: 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester 5-tert-butyl-2-methyl-pyrazole-3-carboxylic acid ethyl ester (2.10 g, To a solution of 10.0 mmol) in DCM (25 mL) was slowly added sulfuryl chloride (1.05 mL, 13.0 mmol) under Ar. After stirring at room temperature for 3 h under Ar, the resulting mixture was treated with DCM (30 mL), washed with ice H ₂ O, saturated aqueous NaHCO ₃ and brine, and dried over Na ₂ SO ₄ . . Removal of the solvent under reduced pressure yielded the title compound as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.40 (q, J = 7.2 Hz, 2H), 4.07 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H) , 1.40 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₁₁ H ₁₇ ClN ₂ O ₂ : 245.1 (M + H), found: 245.1.

Step B: 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester ( Prepared as described in the previous step, a solution of 2.20 g, 9.00 mmol) and 3N aqueous NaOH (7.50 mL, 22.5 mmol) in MeOH (40 mL) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was treated with H ₂ O (30 mL) and washed with Et ₂ O. The aqueous layer was then acidified to pH 7 with 2N aqueous HCl and extracted with DCM. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to yield the title compound as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 10.41 (brs, 1H), 4.12 (s, 3H), 1.42 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₉ H ₁₃ ClN ₂ O ₂ : 217.1 (M + H), found: 217.1.

(Example C)
5-tert-butyl-4-cyano-2-methyl-2H-pyrazole-3-carboxylic acid

Step A: 4-Bromo-5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester 5-tert-butyl-2-methyl-pyrazole-3-carboxylic acid ethyl ester (2.00 g, To a solution of a mixture of 9.51 mmol) and K ₂ CO ₃ (3.94 g, 28.5 mmol) in DCM (120 mL) was slowly added Br ₂ (1.46 mL, 28.5 mmol) in the dark under Ar. . After stirring at room temperature for 3 hours under Ar, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ (50 mL). The organic layer was separated and washed with H ₂ O (50 mL) and brine (50 mL), then dried over Na ₂ SO ₄ . Removal of the solvent under reduced pressure yielded a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.40 (q, J = 7.1 Hz, 2H), 4.08 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H) , 1.42 (m, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₁₁ H ₁₇ BrN ₂ O ₂ : 289.1 (M + H), found: 289.1.

Step B: Ethyl 5-tert-butyl-4-cyano-2-methyl-2H-pyrazole-3-carboxylic acid ethyl 4-bromo-5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylate A solution of ester (1.00 g, 3.46 mmol) and CuCN (372 mg, 4.15 mmol) in NMP (10 mL) was stirred at 200 ° C. for 1 hour under microwave irradiation. After cooling to room temperature, the mixture was treated with DCM (100 mL) and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (0: 100-10: 90 EtOAc-hexanes) to yield the title compound as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.45 (q, J = 7.2 Hz, 2H), 4.14 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H) , 1.43 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₁₂ H ₁₇ N ₃ O ₂ : 236.1 (M + H), found: 236.1.

Step C: 5-tert-Butyl-4-cyano-2-methyl-2H-pyrazole-3-carboxylic acid Using the procedure for Step B of Example A above, the title compound was converted to 5-tert-butyl-4 -Cyano-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (610 mg, 2.59 mmol as described in the above step) and 1.0 N aqueous NaOH (4.00 mL, 4.00 mmol) in MeOH ( 10 mL) solution. The title compound was obtained as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.17 (s, 3H), 1.45 (s, 9H).

(Example D)
Step B: 5-tert-butyl-4-fluoro-2-methyl-2H-pyrazole-3-carboxylic acid

Step A: 5-tert-butyl-4-fluoro-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (210 mg, 1.00 mmol) was added dropwise to a stirred solution of SELECTFLUOR® (531 mg, 1.50 mmol) in anhydrous acetonitrile (4 mL) under Ar atmosphere. The resulting mixture was then stirred at 80 ° C. for 12 hours, then cooled to room temperature, diluted with EtOAc (2 mL) and filtered. The solvent was removed under reduced pressure and the resulting residue was chromatographed on a 24 g pre-packed SiO ₂ column eluting with 0: 1-1: 4 EtOAc / hexane to give 5-tert-butyl. This gave -4-fluoro-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester. ¹ H-NMR H-NMR (400 MHz, CDCl ₃ ) δ: 4.37 (q, J = 7.2 Hz, 2H), 4.03 (d, J = 1.0 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.34 (s, 9H).

Step B: 5-tert-butyl-4-fluoro-2-methyl-2H-pyrazole-3-carboxylic acid 5-tert-butyl-4-fluoro-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester ( 61.4 mg, 0.269 mmol, prepared as described in the previous step) was dissolved in MeOH (1 mL), followed by addition of 2 M NaOH (175 μL, 0.350 mmol). The resulting mixture was stirred at room temperature for 18 hours and the solvent was removed under reduced pressure. The resulting residue was dissolved in H ₂ O (10 mL) and acidified to pH˜2 using 3M HCl. The aqueous layer was extracted with DCM (3 × 5 mL) and the combined organic extracts were dried over MgSO ₄ and filtered. Removal of the solvent under reduced pressure yielded 5-tert-butyl-4-fluoro-2-methyl-2H-pyrazole-3-carboxylic acid. ¹ H-NMR H-NMR (400 MHz, CDCl ₃ ) δ: 9.89 (br.s., 1H), 4.06 (d, J = 1.0 Hz, 3H), 1.36 (s, 9H).

(Example E)
5-tert-butyl-4-methoxy-2-methyl-2H-pyrazole-3-carboxylic acid

Step A: 5-tert-butyl-4-methoxy-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester [Bis (trifluoroacetoxy) iodo] benzene (430 mg, 1.00 mmol) in anhydrous MeOH (4 mL) And the resulting solution was stirred at room temperature for 3 minutes. BF ₃ · OEt ₂ (0.123 mL, 1.00 mmol) was then added via syringe. Ethyl trimethylacetopyruvate (200 mg, 1.00 mmol) was added dropwise via syringe and the resulting mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure and the resulting residue was dissolved in EtOH (2 mL). CH ₃ NHNH ₂ (52.6 μL, 1.00 mmol) was added via syringe and the resulting mixture was stirred at 80 ° C. for 8 hours. The solvent was removed under reduced pressure and the resulting residue was chromatographed on a 24 g pre-packed SiO ₂ column eluting with 0: 1 to 3: 7 EtOAc / hexane to give 5-tert-butyl. This gave -4-methoxy-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.39 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H), 3.83 (s, 3H), 1.42 (t , J = 7.2 Hz, 3H), 1.34 (s, 9H).

Step B: 5-tert-butyl-4-methoxy-2-methyl-2H-pyrazole-3-carboxylic acid 5-tert-butyl-4-methoxy-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester ( 52.8 mg, 0.220 mmol, prepared as described in the previous step) was dissolved in MeOH (1 mL), followed by addition of 2 M NaOH (143 μL, 0.286 mmol). The resulting mixture was stirred at room temperature for 18 hours and the solvent was removed under reduced pressure. The residue was dissolved in H ₂ O (10 mL) and acidified to pH˜2 using 3M HCl. The aqueous layer was extracted with EtOAc (3 × 5 mL) and the combined organic extracts were dried over MgSO ₄ and filtered. Removal of the solvent under reduced pressure yielded 5-tert-butyl-4-methoxy-2-methyl-2H-pyrazole-3-carboxylic acid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 11.65 (br.s., 1H), 4.08 (s, 3H), 3.89 (s, 3H), 1.37 (s, 9H) .

  Note: The use of this material in the subsequent step led to the conclusion that the product was contaminated with a small amount of 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid. This was suspected to be the result of the presence of a small amount of 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester brought from step A above, After use, it was totally unavailable to confirm the suspicion.

(Example F)
4-Chloro-5- (2-fluoro-1,1-dimethyl-ethyl) -2-methyl-2H-pyrazole-3-carboxylic acid

Step A: 5- (2-Fluoro-1,1-dimethyl-ethyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester NaOEt (3.15 mL of 21 wt% EtOH solution, 8.43 mmol). Dissolved in anhydrous toluene (10 mL) and (CO ₂ CH ₂ CH ₃ ) ₂ (0.881 mL, 6.49 mmol) was added. 4,4,4-Trifluoro-3,3-dimethyl-2-butanone (1.00 g, 6.49 mmol) was added and the resulting mixture was stirred at room temperature for 24 hours. The resulting mixture was then acidified to pH˜5 using 3M aqueous HCl and the aqueous phase was extracted with EtOAc (3 × 40 mL). The combined extracts were dried over MgSO ₄ and filtered. The solvent was removed under reduced pressure.

The resulting residue was dissolved in absolute EtOH (20 mL) and CH ₃ NHNH ₂ (0.342 mL, 6.49 mmol) was added dropwise to the stirred mixture via syringe. The resulting mixture was heated to 80 ° C. for 16 hours and then cooled to room temperature. The solvent was removed under reduced pressure and the resulting residue was chromatographed using a 70 g pre-packed SiO ₂ column eluting with 0: 1-1: 4 EtOAc / hexane to give 5- (2 -Fluoro-1,1-dimethyl-ethyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.74 (s, 1H), 4.38 (d, J = 48 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 4 .13 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H), 1.34 (d, J = 1.7 Hz, 6H). ¹⁹ F NMR (376 MHz, ¹ H coupling, CDCl ₃ ) δ: -221 (t, J = 48 Hz, 1F).

Note: The ¹ H-NMR spectrum of the product showed the presence of only one fluoro, so it was believed that the starting ketone purchased was inadequate and in fact 4-fluoro-3,3- Although believed to be dimethyl-2-butanone, this starting material was completely unavailable to confirm this suspicion.

Step B: 4-Chloro-5- (2-fluoro-1,1-dimethyl-ethyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester 5- (2-fluoro-1,1-dimethyl- Ethyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (722 mg, 3.16 mmol, prepared as described in the previous step) was dissolved in DCM (5 mL) and SO ₂ Cl ₂ (0. 256 mL, 3.16 mmol) was added dropwise to the stirred solution. The resulting mixture was stirred at room temperature for 16 hours and the solvent was removed under reduced pressure. The resulting residue was chromatographed on a 40 g pre-packed SiO ₂ column eluting with 0: 1-1: 4 EtOAc / heptane to give 4-chloro-5- (2-fluoro-1, 1-Dimethyl-ethyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.59 (d, J = 47 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 4.08 (s, 3H), 1 .43 (d, J = 1.7 Hz, 6H), 1.41 (t, J = 7.2 Hz, 3H).

Step C: 4-chloro-5- (2-fluoro-1,1-dimethyl-ethyl) -2-methyl-2H-pyrazole-3-carboxylic acid 4-chloro-5- (2-fluoro-1,1- Dimethyl-ethyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (738 mg, 2.81 mmol, prepared as described in the previous step) was dissolved in MeOH (3 mL) and 2M NaOH (1 .83 mL, 3.65 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours and the solvent was removed under reduced pressure. The resulting residue was dissolved in H ₂ O (10 mL) and then acidified to pH˜2 with concentrated HCl. The product was extracted from the solution as an oil and allowed to stand to solidify. The solid was isolated by filtration, washed with H ₂ O (2 × 20 mL) and dried under high vacuum to give 4-chloro-5- (2-fluoro-1,1-dimethyl-ethyl) -2- This gave methyl-2H-pyrazole-3-carboxylic acid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 13.89 (br.s., 1H), 4.56 (d, J = 48 Hz, 2H), 4.00 (s, 3H), 1. 35 (d, J = 1.2 Hz, 6H).

(Example G)
1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid

According to the procedure described in PCT International Publication No. 2007/107470 (Anderson, KW, et al., Published on Sep. 27, 2007), as described in steps 2 and 3 (p97-98) of Example 54. And using triethylamine in place of the sodium acetate reagent in step 2, methyl acetoacetate (1.14 mL, 10.6 mmol), DMFDMA (1.48 mL, 11.1 mmol) and tert-butylhydrazine hydrochloride ( 1.32 g, 10.6 mmol) and TEA (4.43 mL, 31.8 mmol) were used to prepare the title compound and 0: 1 to 3: 7 EtOAc / heptane using an 80 g pre-packed SiO ₂ column. Followed by chromatography eluting with methyl 1-tert-butyl-5-methyl-1H- Resulting in a Razoru-4-carboxylic acid salt. This material was used directly in the next step without further purification. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.78 (s, 1H), 3.80 (s, 3H), 2.75 (s, 3H), 1.66 (s, 9H).

A solution of methyl 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylate in MeOH (20 mL) was treated with 2M aqueous NaOH (7.95 mL, 15.9 mmol) at room temperature for 48 hours. The solvent was removed under reduced pressure and the resulting residue was dissolved in H ₂ O (20 mL). The resulting solution was then acidified to pH˜2 using 2M HCl. The resulting precipitate was isolated by filtration, washed once with H ₂ O (20 mL), and the solid was dried under high vacuum to give 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid. An acid was produced. ¹ H-NMR (400 MHz, d ₆ -DMSO) δ: 12.16 (br.s., 1H), 7.67 (s, 1H), 2.69 (s, 3H), 1.59 (s, 9H).

(Example H)
2-Methyl-6,6-spirocyclohexyl-2,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid

Step A: 2-Methyl-2H-6,6-spirocyclohexyl-2,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid ethyl ester EtOH of NaOEt (2.5 mL, 6.5 mmol, 21% EtOH solution) at −10 ° C., spiro [4.5] decan-1-one (432 mg, 2.83 mmol, Molander, GA, et al., J. Org. Chem., 1993, Prepared as described in Vol. After 15 minutes, the resulting mixture was allowed to warm to room temperature and then stirred for 6 hours. The resulting mixture was treated with 1N aqueous HCl (10 mL) and the product was extracted three times with 20 mL DCM. The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was dissolved in EtOH (10 mL) and HOAc (2 mL). To this mixture was added anhydrous hydrazine (0.46 mL, 14 mmol) dropwise. The resulting mixture was stirred overnight at room temperature. Water (20 mL) was added and the product was extracted twice with 20 mL EtOAc. The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was purified on silica (0: 100-100: 0 v / v EtOAc-hexane) to give 6,6-spirocyclohexyl-2,4,5,6-tetrahydro-cyclo as a viscous oil. This yielded pentapyrazole-3-carboxylic acid ethyl ester. ¹ H-NMR (400 MHz, CDCl ₃ ). δ: 4.34 (q, J = 7.2 Hz, 2H), 2.72 to 2.79 (m, 2H), 2.22 to 2.29 (m, 2H), 1.40 to 1.80 (M, 13H), 1.35 (t, J = 7.2 Hz, 3H).

To a solution of 6,6-spirocyclohexyl-2,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid ethyl ester (185 mg, 0.747 mmol, prepared as above) in DMF (10 mL) was added K ₂ CO. ₃ (206 mg, 1.49 mmol) was added. The resulting mixture was stirred for 10 minutes and then treated with CH ₃ I (0.046 mL, 1.49 mmol). The resulting mixture was stirred overnight and then poured into water (10 mL). The product was extracted 3 times with EtOAc (20 mL). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was purified on silica gel (0: 100-100: 0 EtOAc-hexanes) to yield the title compound. ¹ H-NMR (400 MHz; CDCl ₃ ) δ: 4.22 (q, J = 7.1 Hz, 2H), 4.05 (s, 3H), 2.66 (t, J = 7.1 Hz, 2H) , 2.12 to 2.17 (m, 2H), 1.59 to 1.72 (m, 4H), 1.36 to 1.48 (m, 6H), 1.27 (t, J = 7. 1Hz, 3H).

Step B: 2-Methyl-2H-6,6-spirocyclohexyl-2,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid 2-methyl-2H-6,6-spirocyclohexyl-2,4 , 5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid ethyl ester (prepared as described in previous step, 124 mg, 0.472 mmol) in MeOH (6 mL) in LiOH (56.5 mg, 2.36 mmol). ) Followed by water (2 mL). The resulting mixture was stirred overnight at reflux. The resulting mixture was then allowed to cool to room temperature and MeOH was removed under reduced pressure. The resulting mixture was acidified with 1N aqueous HCl and the product was extracted three times with DCM (30 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 10.77 (br s, 1H), 4.17 (s, 3H), 2.81 (t, J = 7.1 Hz, 2H), 2.13 2.35 (m, 2H), 1.64 to 1.83 (m, 4H), 1.39 to 1.62 (m, 6H).

Example I
3-tert-butylisoxazole-5-carboxylic acid

Step A: 3-tert-Butylisoxazole-5-carboxylic acid methyl ester Pivalaldehyde (1.10 mL, 10.0 mmol) was dissolved in anhydrous DMF (10 mL) and NH ₂ OH · H ₂ O (0.590 mL of 55 % Aqueous solution, 10.5 mmol) was added via syringe. The resulting mixture was stirred at room temperature for 4 hours, NCS (1.40 g, 10.5 mmol) was added in portions and the resulting mixture was stirred at room temperature for 1 hour. CuSO ₄ .5H ₂ O (75.0 mg, 0.300 mmol), methyl propiolate (1.07 mL, 12.0 mmol) and H ₂ O (5 mL) were added, followed by Cu powder (25.0 mg, 0. 393 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours and quenched with dilute aqueous NH ₄ OH (2 mL). The aqueous solution was extracted with hexane (3 × 30 mL), then the combined organic extracts were dried over MgSO ₄ and filtered. The solvent was removed under reduced pressure to yield the title compound as a colorless oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.88 (s, 1H), 3.96 (s, 3H), 1.36 (s, 9H).

Step B: 3-tert-Butylisoxazole-5-carboxylic acid According to the procedure described in Step B of Example A above, 3-tert-butylisoxazole-5-carboxylic acid methyl ester (1.68 g, 9.19 mmol). , Prepared as described in the previous step) and 2.5 M aqueous NaOH (5.00 mL, 12.5 mmol) to prepare the title compound as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.99 (s, 1H), 1.38 (s, 9H).

(Example J)
3-tert-butyl-4-cyano-isoxazole-5-carboxylic acid

Step A: 3-tert-Butyl-4-cyano-4,5-dihydro-isoxazole-5-carboxylic acid ethyl ester Pivalaldehyde (1.63 mL, 15.0 mmol) was dissolved in anhydrous DMF (15 mL) and H _2. NOH.xH ₂ O (0.860 mL of 55% aqueous solution, 15.4 mmol) was added via syringe. The resulting mixture was stirred at room temperature for 1 hour and NCS (2.06 g, 15.4 mmol) was added as a solid. The resulting mixture was stirred at room temperature for 1 hour and DCM (50 mL) was added. The resulting solution was placed in a dropping funnel and added dropwise over 4 hours to a stirred DCM (40 mL) solution of ethylcis-β-cyanoacrylate (1.98 mL, 16.5 mmol) and TEA (4.18 mL, 30.0 mmol). . After the addition was complete, the resulting mixture was stirred at room temperature for 8 hours and then concentrated under reduced pressure. The resulting residue was dissolved in DCM (50 mL), washed with H ₂ O (3 × 30 mL) and brine (30 mL), dried over anhydrous MgSO ₄ and filtered. The solvent was removed under reduced pressure. The resulting residue was chromatographed on a 40 g pre-packed SiO ₂ column eluting with 0: 1 to 3: 7 EtOAc / hexane to give 3-tert-butyl-4-cyano-4,5- This gave a mixture of ethyl cis-β-cyanoacrylate mixed with dihydro-isoxazole-5-carboxylic acid ethyl ester (approximately 1: 1.6 as determined by ¹ H-NMR). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 5.22 (d, J = 5.1 Hz, 1H), 4.55 (d, J = 5.1 Hz, 1H), 4.25 to 4.32 ( m, 2H), 1.35 (s, 9H), 1.31-1.36 (t, J = 7.1 Hz, 3H).

Step B: 3-tert-butyl-4-cyano-isoxazole-5-carboxylic acid ethyl ester 3-tert-butyl-4-cyano-4,5-dihydro-isoxazole-5-carboxylic acid ethyl ester (1. 51 g, 2.56 mmol (corrected for measured purity), prepared as described in the previous step) was dissolved in toluene (10 mL) and DDQ (2.41 g, 10.6 mmol) was added as a solid. The resulting mixture was heated to 110 ° C. for 16 hours, then cooled to room temperature and diluted with hexane (2 mL). The resulting suspension was filtered and the precipitate was washed once with toluene (4 mL). The filtrates were combined and concentrated under reduced pressure. The resulting residue was chromatographed on a 24 g pre-packed SiO ₂ column eluting with 0: 1-1: 4 EtOAc-hexane to give 3-tert-butyl-4-cyano-isoxazole- This gave 5-carboxylic acid ethyl ester. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.52 (q, J = 7.1 Hz, 2H), 1.49 (s, 9H), 1.43-1.48 (t, J = 7. 1Hz, 3H).

Step C: 3-tert-butyl-4-cyano-isoxazole-5-carboxylic acid 3-tert-butyl-4-cyano-isoxazole-5-carboxylic acid ethyl ester (809 mg, 3.64 mmol, in the previous step Prepared as described) in MeOH (9 mL) and 1M LiOH (4.73 mL, 4.73 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The resulting residue was dissolved in H ₂ O (10 mL) and extracted with DCM (3 × 10 mL). The aqueous layer was acidified with 3M aqueous HCl to pH ˜2, and the product was extracted with EtOAc (3 × 20 mL). The combined extracts were dried over MgSO ₄ and filtered. Removal of the solvent under reduced pressure yielded 3-tert-butyl-4-cyano-isoxazole-5-carboxylic acid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 9.90 (br.s., 1H), 1.50 (s, 9H).

(Example K)
5-Bromo-4-tert-butyl-furan-2-carboxylic acid

Step A: Methyl 5-bromo-4-tert-butyl-furan-2-carboxylate Gilman, H .; , Et al. , J .; Am. Chem. Soc. , 1939, Vol. 61, pp 473-478, more specifically according to the general procedure on pages 467-477, methyl 5-bromofuran-2-carboxylate (5.00 g, 24.4 mmol) and 1-bromooctadecane (8 .13 g, 24.4 mmol) and anhydrous AlCl ₃ (6.50 g, 48.8 mmol) in CS ₂ (50 mL) were prepared to give the title compound as methyl 5-bromo-4-tert-butyl-furan-2- Carboxylate was produced. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.12 (s, 1H), 3.88 (s, 3H), 1.33 (s, 9H).

Step B: 5-Bromo-4-tert-butyl-furan-2-carboxylic acid methyl 5-bromo-4-tert-butyl-furan-2-carboxylate (1.45 g, 5.57 mmol, as described in the previous step. Treated with a mixed solvent solution of THF (15 mL), MeOH (10 mL) and H ₂ O (5 mL) with 3M aqueous NaOH (3.00 mL, 9.00 mmol), and the resulting mixture is treated with Stir at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was dissolved in H ₂ O (60 mL) and extracted with Et ₂ O (2 × 30 mL). The aqueous layer was acidified to pH˜2 using 2M HCl. The precipitate was isolated by filtration, washed with H ₂ O (20mL), was allowed to air dry, 5-bromo -4-tert-butyl - resulting furan-2-carboxylic acid. The filtrate was extracted with EtOAc (3 × 20 mL) and the combined organic extracts were dried over MgSO ₄ and filtered. Removal of the solvent under reduced pressure yielded a second crop of 5-bromo-4-tert-butyl-furan-2-carboxylic acid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.25 (s, 1H), 1.35 (s, 9H).

(Example L)
4-tert-butyl-furan-2-carboxylic acid

Gilman, H.C. , Et al. , J .; Am. Chem. Soc. , 1935, Vol. 57, pp 909-912, and more specifically as described on page 910, 5-bromo-4-tert-butyl-furan-2-carboxylic acid (500 mg, 2.02 mmol, carried out). NH ₃ diluted aqueous solution (prepared as described in Step B of Example K) (made by diluting 1 mL 29.3% aqueous NH ₃ with 9 mL H ₂ O) Zn powder (265 mg, 4.05 mmol) The title compound was prepared by treatment with to yield the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.40 (d, J = 1.0 Hz, 1H), 7.28 (d, J = 1.2 Hz, 1H), 1.26 (s, 9H) .

(Example M)
5-Isopropylthiophene-3-carboxylic acid

  Stanetti, et al. , Monatshefte fur Chemie (1989), 120 (1), 65-72, modified the procedure for the synthesis of compounds (21) and (22) on page 70 to replace pentyl nitrite tert-nitrite. The title compound was prepared by using butyl.

Example N
4-Isopropyl-thiophene-2-carboxylic acid

  PCT International Publication No. 2009/098448 (A1) (Alcaraz, L., et al., Published on Aug. 13, 2009) described in pages (282) to (283) of Example 74, steps (a) and (b). The title compound was prepared according to the procedure.

(Example O)
4-tert-butyl-1-methyl-1H-imidazole-2-carboxylic acid

Step A: 3,3-Dimethyl-1-methylamino-butan-2-one hydrochloride A solution of 1-bromopinacolone (5.00 g, 27.9 mmol) in acetonitrile (8 mL) was methylamine (6.98 mL, 55.55). 9 mmol, about 8M anhydrous alcohol solution) was added over 5 min at 0 ° C. under Ar. The resulting mixture was stirred at 0 ° C. for 3 hours. Anhydrous diethyl ether (200 mL) was added and the resulting white solid was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was treated with ethanol (20 mL). To the resulting solution was added 1.0 N HCl in diethyl ether (22.3 mL) at 0 ° C. over 10 minutes. The resulting mixture was treated with diethyl ether (150 mL) and the resulting white solid was collected by filtration and dried under reduced pressure to yield 3,3-dimethyl-1-methylamino-butane-2 as a white solid. -On hydrochloride was produced. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 4.28 (s, 2H), 2.72 (s, 3H), 1.21 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₇ H ₁₅ NO: 130.1 (M + H), found: 130.1.

Step B: 4-tert-Butyl-1-methyl-1H-imidazole 3,3-dimethyl-1-methylamino-butan-2-one hydrochloride (1.00 g, 6.04 mmol, as described in the previous step. Prepared formamide (12 mL, 302 mmol) was stirred at 200 ° C. for 3 hours under microwave irradiation. After cooling to room temperature, the resulting mixture was treated with 3N NaOH (30 mL) and extracted with toluene (3 × 50 mL). The combined organic layers were washed with H ₂ O (30 mL), brine (30 mL) and then dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (0: 100-10: 90 MeOH / DCM) to give 4-tert-butyl-1-methyl- as a colorless oil. 1H-imidazole was produced. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.32 (s, 1H), 6.55 (s, 1H), 3.59 (s, 3H), 1.25 (s, 9H). Mass spectrum (LCMS, ESI pos.) Calculated for C ₈ H ₁₄ N ₂ : 139.1 (M + H), found: 139.1.

Step C: 4-tert-butyl-1-methyl-1H-imidazole-2-carboxylic acid methyl ester 4-tert-butyl-1-methyl-1H-imidazole (800 mg, 5.79 mmol, as described in the previous step. Methyl chloroformate (0.890 mL, 11.6 mmol) was slowly added to a solution of a mixture of triethylamine (2.00 mL, 14.4 mmol) in acetonitrile (10 mL) at −30 ° C. under Ar. The resulting mixture was warmed to room temperature and continued to stir for 16 hours. The resulting mixture was then treated with EtOAc (50 mL), washed with H ₂ O (2 × 20 mL), brine (20 mL), and then dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (0: 100-10: 90 MeOH / DCM) to give 4-tert-butyl-1-methyl- as a colorless oil. 1H-imidazole-2-carboxylic acid methyl ester was produced. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.78 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 1.30 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₁₀ H ₁₆ N ₂ O ₂ : 197.1 (M + H), found: 197.1.

Step D: 4-tert-butyl-1-methyl-1H-imidazole-2-carboxylic acid 4-tert-butyl-1-methyl-1H-imidazole-2-carboxylic acid methyl ester (680 mg, 3.46 mmol, previous A solution of 1N NaOH (3.81 mL, 3.81 mmol) in MeOH (10 mL) was stirred at room temperature for 2 hours. To the resulting mixture was then added 1.0 N aqueous HCl (3.85 mL). The solvent was removed under reduced pressure and the residue was treated with DCM (50 mL). The solid was filtered through diatomaceous earth and washed with DCM. The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to yield 4-tert-butyl-1-methyl-1H-imidazole-2-carboxylic acid as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.00 (s, 1H), 4.18 (s, 3H), 1.49 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₉ H ₁₄ N ₂ O ₂ : 183.1 (M + H), found: 183.1.

  Examples 1-35 that follow herein describe the synthesis of representative compounds of formula (I).

Example 1
2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -7-chloro-5- (2-trifluoromethyl-phenyl-1H-imidazo [4,5-b Pyridine sodium salt (Compound # 5)

Step A: 4-Chloro-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine 4,6-dichloro-pyridin-2-ylamine (1.00 g, 6.14 mmol) in DME (75 mL) / The water (50 mL) solution was treated with Cs ₂ CO ₃ (6.00 g, 18.4 mmol) and 2- (trifluoromethyl) phenylboronic acid (1.52 g, 7.98 mmol). The resulting mixture was degassed by heating under a stream of Ar. Cl ₂ Pd (dppf) · DCM (270 mg, 0.368 mmol) was added and the mixture was heated to 80 ° C. for 24 hours. The cooled mixture was diluted with EtOAc (70 mL) and washed twice with water (50 mL). The combined aqueous layer was extracted twice with EtOAc (50 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 115 g SEPRA Si35 SPE silica column (flow rate = 30 mL / min; eluent = EtOAc-hexane, 1:19 over 15 minutes, 1:19 to 1: 3 over 40 minutes, then product 1: 3 until elution occurred, yielding 4-chloro-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine as an off-white solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.74 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 1.5 Hz, 1H), 6.53 (d, J = 1.5 Hz, 1H) ), 4.59 (br.s., 2H). Mass spectrum (LCMS, ESI pos.): Calculated for C ₁₂ H ₈ N ₂ ClF ₃ : 273.0 (M + H); found: 273.0.

Step B: 4-Chloro-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine 4-chloro-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine ( 617.5 mg, 2.27 mmol, prepared as described in the above step) was cooled to 0 ° C. and treated slowly with H ₂ SO ₄ (10 mL). The mixture was stirred at 0 ° C. for 1 hour. Nitric acid (133 μL, 2.94 mmol) was added slowly and the mixture continued to stir at 0 ° C. for an additional 1.5 hours. Ice (50 mL) was added. The formed precipitate was filtered, dissolved in DCM (70 mL) and washed with saturated aqueous NaHCO ₃ (70 mL). The aqueous layer was extracted with DCM (30 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 40 g SEPRA Si 35 SPE column (flow rate = 20 mL / min; eluent = EtOAc-hexane, 1:19 over 15 minutes, then 1:19 to 1: 3 over 40 minutes). This gave 4-chloro-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine as a yellow solid. The basic mother liquor and acidic filtrate were carefully combined, basified with 1N aqueous NaOH and extracted twice with DCM (100 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure to yield additional product. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.76 to 7.90 (m, 1H), 7.55 to 7.71 (m, 2H), 7.46 (d, J = 7.3 Hz, 1H), 6.93 (s, 1H), 6.11 (br.s., 2H). Mass spectrum (. LCMS, APCI pos): Calculated for _{C 12 H 7 N 3 O 2} ClF 3: 318.0 (M + H); Found: 318.0.

Step C: 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [4-chloro-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridine-2- Yl] -amide 4-chloro-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine (87.5 mg, 0.275 mmol, prepared as described in Step B above) THF The (10 mL) solution was treated with NaH (33.1 mg, 0.826 mmol, 60% dispersion in oil) and the mixture was allowed to stir at room temperature for 1 hour. At the same time, 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (77.6 mg, 0.358 mmol, prepared as described in Example B above) in DCM (10 mL) Was treated with oxalyl chloride (31.2 μL, 0.358 mmol) and DMF (2 drops) and the mixture was stirred at room temperature for 1 h. The volatile component was removed under reduced pressure to yield 5-tert-butyl-4-methyl-2-Hydroxy-2H-pyrazole-3-carbonyl chloride as a solid. The solid was taken up in anhydrous THF (6 mL) and the acid chloride solution was then added to the sodium anilide solution as prepared above and the resulting mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aqueous NH ₄ Cl (50 mL) and extracted twice with EtOAc (40 mL and 25 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on an 8 g SEPRA Si 35 SPE column (flow rate = 10 mL / min; eluent = EtOAc-hexane, 1:19 over 15 minutes, then 1:19 to 1: 3 over 40 minutes). However, as a colorless glassy solid, 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [4-chloro-3-nitro-6- (2-trifluoromethyl-phenyl)- Gave pyridin-2-yl] -amide. Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₁ H ₁₈ N ₅ O ₃ Cl ₂ F ₃ : 516.2 (M + H); found: 516.2.

Step D: 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-amino-4-chloro-6- (2-trifluoromethyl-phenyl) -pyridine-2- Yl] -amide 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [4-chloro-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridine-2 -Il] -amide (109 mg, 0.211 mmol, prepared as described in the previous step) in EtOH (5 mL) / water (2.5 mL) was added NH ₄ Cl (113 mg, 2.11 mmol) and iron powder ( 58.9 mg, 1.06 mmol). The mixture was heated to 60 ° C. for 5 hours and then EtOH was evaporated under reduced pressure. The remaining aqueous mixture was diluted with water (30 mL) and extracted twice with EtOAc (25 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 12 g SEPRA Si 35 SPE column (flow rate = 15 mL / min; eluent = EtOAc-hexane, 1:99 over 10 minutes, then 1:99 to 1: 4 over 40 minutes). However, as a colorless glassy solid, 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-amino-4-chloro-6- (2-trifluoromethyl-phenyl)- Gave pyridin-2-yl] -amide. Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₁ H ₂₀ N ₅ OCl ₂ F ₃ : 486.1 (M + H); found: 486.2.

Step E: 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -7-chloro-5- (2-trifluoromethyl-phenyl-1H-imidazo [4 5-b] pyridine 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-amino-4-chloro-6- (2-trifluoromethyl-phenyl) -pyridine- A solution of 2-yl] -amide (54.0 mg, 0.111 mmol, prepared as described above in Step D) in 1,4-dioxane (10 mL) is treated with CSA (51.6 mg, 0.222 mmol), The mixture was heated under reflux condenser for 3 hours to 100 ° C. The cooled resulting mixture was diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO ₃ (20 mL). The organic extract was dried over MgSO ₄ and concentrated under reduced pressure The residue was purified on an 8 g SEPRA Si35 SPE column (flow rate = 10 mL / min; eluent = EtOAc-hexane, 1:99 over 10 min, then 1: 99 to 1: 4 over 40 minutes) where 28.2 mg (54%) 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)- This gave 7-chloro-5- (2-trifluoromethyl-phenyl-1H-imidazo [4,5-b] pyridine. Mass spectrum (LCMS, ESI pos.): C ₂₁ H ₁₈ N ₅ Cl ₂ F ₃ Calculated value: 468.1 (M + H); measured value: 468.2.

Step F: 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -7-chloro-5- (2-trifluoromethyl-phenyl-1H-imidazo [4 5-b] pyridine sodium salt 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -7-chloro-5- (2-trifluoromethyl-phenyl-1H- Imidazo [4,5-b] pyridine (28.2 mg, 0.0602 mmol) was dissolved in anhydrous MeOH (4 mL) and treated with NaOMe (120 μL, 0.060 mmol, 0.5 M MeOH solution) at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to give 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-i as a white solid. ) -7-chloro-5- (. 2-trifluoromethyl - resulted phenyl -1H- imidazo [4,5-b] pyridine sodium salt ^{1 H-NMR (400MHz, CD} 3 OD) δ: 7.69 (D, J = 7.6 Hz, 1H), 7.55 to 7.61 (m, 1H), 7.45 to 7.52 (m, 2H), 7.01 (s, 1H), 3.81 (S, 3H), 1.34 (s, 9H).

  Following the procedures described in Example 1 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 2)
8- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6-methyl-2- (2-trifluoromethyl-phenyl) -7H-purine hydrochloride (compound # 3)

Step A: 5-tert-butyl-4-chloro-2-methyl-2H- [pyrazole-3-carboxylic acid [6-methyl-5-nitro-2- (2-trifluoromethyl-phenyl) -pyrimidine-4 -Yl] -amido 6-methyl-5-nitro-2- (2-trifluoromethyl-phenyl) -pyrimidin-4-ylamine (109 mg, 0.365 mmol, prepared as described in Step A of Example 1) Of THF (10 mL) was treated with NaH (43.9 mg, 1.10 mmol, 60% dispersion in oil) and the mixture was allowed to stir at room temperature for 1 h. Simultaneously, a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (103 mg, 0.475 mmol, prepared as described above in Example B) in DCM (10 mL) was chlorinated. Treated with oxalyl (41.5 μL, 0.475 mmol) and DMF (2 drops) and the mixture was stirred at room temperature for 1 hour. Volatile components were removed under reduced pressure and the residue was taken up in anhydrous THF (6 mL). The acid chloride solution prepared as above was added to the sodium anilide solution and the resulting mixture was stirred at room temperature for 15 minutes. The resulting mixture was then treated with saturated aqueous NH ₄ Cl (50 mL) and extracted twice with EtOAc (50 mL). The residue was purified on a 24 g SEPRA Si 50 SPE column (flow rate = 20 mL / min; eluent = EtOAc-hexane, 1:99 over 15 minutes, then 1:99 to 3: 7 over 40 minutes). However, 5-tert-butyl-4-chloro-2-methyl-2H- [pyrazole-3-carboxylic acid [6-methyl-5-nitro-2- (2-trifluoromethyl-phenyl) -pyrimidine as an off-white solid Yielded -4-yl] -amide. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 9.59 (s, 1H), 7.81 to 7.88 (m, 2H), 7.60 to 7.72 (m, 2H), 4.11 (S, 3H), 2.82 (s, 3H), 1.40 (s, 9H). Mass spectrum (LCMS, APCI pos.): Calculated for C ₂₁ H ₂₀ N ₆ O ₃ ClF ₃ : 497.1 (M + H); found: 497.2.

Step B: 8- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6-methyl-2- (2-trifluoromethyl-phenyl) -7H-purine 5- tert-Butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6-methyl-5-nitro-2- (2-trifluoromethyl-phenyl) -pyrimidin-4-yl] -amide ( A solution of 138 mg, 0.278 mmol, prepared as described in Step A above) in AcOH (10 mL) was treated with iron powder (77.5 mg, 1.39 mmol) and the mixture was heated to 100 ° C. for 4 hours. The cooled mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO ₃ (50 mL). The aqueous layer was re-extracted with EtOAc (50 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 24 g SEPRA Si 50 SPE column (flow rate = 20 mL / min; eluent = EtOAc-hexane, 1: 9 over 15 minutes, then 1: 9 to 2: 3 over 40 minutes). However, 8- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6-methyl-2- (2-trifluoromethyl-phenyl) -7H-purine as a white solid Produced. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 10.66 (br.s., 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.72-7.77 (m, 1H) ), 7.66 (t, J = 7.5 Hz, 1H), 7.54 to 7.62 (m, 1H), 4.40 (s, 3H), 2.95 (s, 3H), 1. 45 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₁ H ₂₀ N ₆ ClF ₃ : 449.1 (M + H); found: 449.1.

Step C: 8- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6-methyl-2- (2-trifluoromethyl-phenyl) -7H-purine hydrochloride 8- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6-methyl-2- (2-trifluoromethyl-phenyl) -7H-purine (99.7 mg, A solution of 0.222 mmol, prepared as in Step B above) in EtOH (6 mL) is treated with HCl (44.4 μL, 0.222 mmol, 5 M IPA solution) at room temperature for 1.5 hours and concentrated under reduced pressure. did. EtOH (0.5 mL) was added and the resulting glassy solid was dissolved using sonication and heating. Hexane (5 mL) was added and the resulting mixture was concentrated under reduced pressure. The resulting foamy solid was triturated with hexane, filtered and air dried to give 8- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6 as a white solid. -Methyl-2- (2-trifluoromethyl-phenyl) -7H-purine hydrochloride was produced. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.82 to 8.03 (m, 2H), 7.65 to 7.82 (m, 2H), 4.39 (s, 3H), 3.34 (Br.s., 3H), 1.45 (s, 9H). Mass spectrum (LCMS, APCI pos.): Calculated for C ₂₁ H ₂₀ N ₆ ClF ₃ : 449.1 (M + H); found: 449.2.

  Following the procedures described in Example 2 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 3)
8- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6-methyl-2- (2-trifluoromethyl-phenyl) -7H-purine sodium salt (compound # 3)

Step A: 6-Methyl-5-nitro-2- (2-trifluoromethyl-phenyl) -pyrimidin-4-ylamine 2-chloro-6-methyl-5-nitro-pyrimidin-4-ylamine (920 mg, 4. 89 mmol) in 1,4-dioxane (50 mL) was added to (2-trifluoromethylphenyl) boronic acid (1.3 g, 6.8 mmol), K ₃ PO ₄ (2.07 g, 9.78 mmol) and (dppf) Treated with PdCl ₂ · DCM (318 mg, 0.487 mmol) and heated to 100 ° C. under Ar for 4 h. The cooled mixture was filtered through a pad of diatomaceous earth, diluted with water and extracted three times with EtOAc. The combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on silica (0: 100 v / v to 100: 0 v / v EtOAc-hexane over 20 minutes) to give 6-methyl-5-nitro-2- (2-trifluoromethyl-phenyl). ) -Pyrimidin-4-ylamine. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.80 (d, J = 7.6 Hz, 1H), 7.71 to 7.75 (m, 1H), 7.65 (t, J = 6. 9 Hz, 1H), 7.57 to 7.62 (m, 1H), 2.84 (s, 3H).

Step B: 8- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6-methyl-2- (2-trifluoromethyl-phenyl) -7H-purine sodium salt Following the procedure as described in steps C, D, E of Example 1 above, 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (108 mg, 0.499 mmol, above described Prepared as described in Example B) and 4-methyl-6-methyl-5-nitro-2- (2-trifluoromethyl-phenyl) -pyrimidin-4-ylamine (149 mg, 0.500 mmol, Example A above) The title compound was prepared as an off-white solid from ¹ H-NMR (400 MHz; CD ₃ OD) δ: 7.78-7.83 (m, 1H), 7.68-7.74 (m, 1H), 7.60-7.67 (m, 2H) ), 2.78-2.85 (m, 3H), 1.44 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₂₁ H ₂₀ ClF ₃ N ₆ : 449.1 (M + H), found: 449.2.

Example 4
2- (3-tert-Butyl-isoxazol-5-yl) -7-chloro-5- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b] pyridine (Compound # 7)

Step A: 3-tert-butyl-isoxazole-5-carboxylic acid [4-chloro-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amide 4-chloro-3 A solution of -nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine (100 mg, 0.315 mmol, prepared as described in step B of Example 1 above) in THF (10 mL) was added NaH ( 37.8 mg, 0.944 mmol, 60% dispersion in oil) and the mixture was allowed to stir at room temperature for 1 hour. Concurrently, a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (69.2 mg, 0.409 mmol, prepared as described in Example I above) in DCM (10 mL) was added to oxalyl chloride (35.7 μL, 0 .409 mmol) and DMF (2 drops) and the resulting mixture was stirred at room temperature for 1 hour. Volatile components were removed under reduced pressure and the residue was taken up in anhydrous THF (6 mL). The acid chloride solution prepared as above was added to the sodium anilide solution and the resulting mixture was stirred at room temperature for 15 minutes. The resulting mixture was then quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted twice with EtOAc (30 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 25 g SEPRA Si 50 SPE column (flow rate = 20 mL / min; eluent = EtOAc-hexane, 1:99 over 10 minutes, then 1:99 to 1: 3 over 40 minutes). Whereupon, 3-tert-butyl-isoxazole-5-carboxylic acid [4-chloro-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amide was produced as a yellow solid. . Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₁ H ₁₆ N ₄ O ₄ ClF ₃ : 469.1 (M + H); found: 469.1.

Step B: 3-tert-butyl-isoxazole-5-carboxylic acid [3-amino-4-chloro-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amide 3-tert-butyl Isoxazole-5-carboxylic acid [4-chloro-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amide (40.7 mg, 0.0868 mmol, in step A above) A solution of EtOH (5 mL) / water (2.5 mL) prepared as described) was treated with ammonium chloride (46.4 mg, 0.868 mmol) and iron powder (24.2 mg, 0.434 mmol) and the mixture was mixed with 50 Stir at 0 ° C. for 3 hours. The cooled mixture was concentrated under reduced pressure and partitioned between EtOAc (25 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 12 g SEPRA Si 50 SPE column (flow rate = 20 mL / min; eluent = EtOAc-hexane, 1:99 over 10 minutes, then 1:99 to 1: 3 over 40 minutes). The result was 3-tert-butyl-isoxazole-5-carboxylic acid [3-amino-4-chloro-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amide as a yellow solid. . Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₁ H ₁₈ N ₄ O ₂ ClF ₃ : 439.1 (M + H); found: 439.1.

Step C: 2- (3-tert-butyl-isoxazol-5-yl) -7-chloro-5- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b] pyridine 3-tert -Butyl-isoxazole-5-carboxylic acid [3-amino-4-chloro-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amide (36.2 mg, 0.0825 mmol, above step A solution of 1,4-dioxane (10 mL) prepared as described in B) with (+)-10-camphorsulfonic acid (38.3 mg, 0.165 mmol) and the mixture heated to 100 ° C. for 5 hours. did. The cooled mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO ₃ (20 mL). The organic extract was dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on an 8 g SEPRA Si 35 SPE column (flow rate = 15 mL / min; eluent = EtOAc-hexane, 1:99 over 10 minutes, then 1:99 to 1: 3 over 40 minutes). However, 2- (3-tert-butyl-isoxazol-5-yl) -7-chloro-5- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b] pyridine was obtained as a white solid. occured. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.77 (d, J = 7.8 Hz, 1H), 7.58 to 7.64 (m, 1H), 7.50 to 7.58 (m, 2H), 7.49 (s, 1H), 7.16 (s, 1H), 1.88 (br.s., 1H), 1.39 (s, 9H). Mass spectrum (. LCMS, APCI pos): Calculated for _{C 20 H 16 N 4 OClF 3} : 421.1 (M + H); Found: 421.1.

(Example 5)
2- (3-tert-Butyl-isoxazol-5-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] -pyridine sodium salt (compound # 8)

Step A: 6-chloro-2-methoxy-3-nitro-pyridin-4-ylamine 2,6-dichloro-3-nitro-pyridin-4-ylamine (733 mg, 3.52 mmol) was fitted with a magnetic stir bar. Placed in a 48 mL pressure vessel and treated with NaOMe (7.05 mL, 3.52 mmol, 0.5 M MeOH solution). The vessel was sealed and heated to 100 ° C. for 2 hours. The cooled mixture was treated with a solution of acetic acid (0.25 mL) in diethyl ether (50 mL). The precipitate was filtered and washed with ether, and the filtrate was concentrated under reduced pressure. The residue was purified on a 40 g SEPRA Si 35 SPE column (flow rate = 25 mL / min; eluent = EtOAc-hexane, 1:19 over 15 minutes, then 1:19 to 1: 4 over 40 minutes). To give 6-chloro-2-methoxy-3-nitro-pyridin-4-ylamine as a pale yellow solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.36 (s, 1H), 6.14 (br.s., 2H), 4.04 (s, 3H).

Step B: 2-Methoxy-3-nitro-6- (2-trifluoromethyl-phenyl) -4-pyridin-4-ylamine 6-chloro-2-methoxy-3-nitro-pyridin-4-ylamine (500 mg, 2.46 mmol, prepared as described in Step A above) in DME (20 mL) / water (6 mL) was added to Cs ₂ CO ₃ (2.40 g, 7.37 mmol) and 2-trifluoromethylphenylboronic acid (560 mg). 2.95 mmol). The resulting mixture was degassed by heating to 80 ° C. under Ar flow. Cl ₂ Pd (dppf) · DCM (121 mg, 0.147 mmol) was added and the mixture was heated to 80 ° C. for 15 hours. The cooled mixture was diluted with water (50 mL) and extracted twice with EtOAc (60 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 24 g SEPRA Si50 SPE column (flow rate = 20 mL / min; eluent = EtOAc-hexane, 1:19 over 5 minutes, then 1:19 to 1: 3 over 40 minutes). This gave 2-methoxy-3-nitro-6- (2-trifluoromethyl-phenyl) -4-pyridin-4-ylamine as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.77 (d, J = 8.3 Hz, 1H), 7.58 to 7.65 (m, 1H), 7.52 to 7.58 (m, 1H), 7.48 (d, J = 7.6 Hz, 1H), 6.42 (s, 1H), 4.03 (s, 3H). Mass spectrum (LCMS, APCI pos.): Calculated for C ₁₃ H ₁₀ N ₃ O ₃ F ₃ : 314.1 (M + H); found: 314.1.

Step C: 3-tert-butyl-isoxazole-5-carboxylic acid [2-methoxy-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-yl] -amide 2-methoxy-3 A solution of -nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-ylamine (163 mg, 0.519 mmol, prepared as described above in Step B) in THF (10 mL) was added NaH (62.2 mg, 1.56 mmol, 60% dispersion in oil) and the mixture was allowed to stir at room temperature for 1 hour. Simultaneously, a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (114 mg, 0.674 mmol, prepared as described in Example I above) in anhydrous DCM (10 mL) was added to oxalyl chloride (58.8 μL, 0. 674 mmol) and DMF (2 drops) and the mixture was stirred at room temperature for 1 h. Volatile components were removed under reduced pressure and the residue was taken up in anhydrous THF (6 mL). The acid chloride solution prepared as above was added to the sodium anilide solution and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted twice with EtOAc (25 mL). The residue was purified on a 12 g SEPRA Si 50 SPE column (flow rate = 15 mL / min; eluent = EtOAc-hexane, 1:99 over 10 minutes, then 1:99 to 1: 4 over 40 minutes). Whereupon, 3-tert-butyl-isoxazole-5-carboxylic acid [2-methoxy-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-yl] -amide was produced as a white solid. . ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 10.62 (s, 1H), 8.39 (s, 1H), 7.82 (d, J = 7.3 Hz, 1H), 7.63-7 .69 (m, 1H), 7.58 to 7.63 (m, 1H), 7.56 (d, J = 7.6 Hz, 1H), 6.98 (s, 1H), 4.09 (s , 3H), 1.38 (s, 9H). Mass spectrum (LCMS, APCI pos.): Calculated for C ₂₁ H ₁₉ N ₄ O ₅ F ₃ : 465.1 (M + H); found: 465.1.

Step D: 2- (3-tert-butyl-isoxazol-5-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] -pyridine 3- tert-Butyl-isoxazole-5-carboxylic acid [2-methoxy-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-yl] -amide (110 mg, 0.237 mmol, Step C above) A solution of AcOH (5 mL) prepared as described in 1) was treated with iron powder (66.1 mg, 1.18 mmol) and the mixture was heated to 100 ° C. for 3 h. AcOH was removed under reduced pressure. The residue was taken up in saturated aqueous NaHCO ₃ (50 mL) and extracted twice with EtOAc (50 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 12 g SEPRA Si 50 SPE column (flow rate = 15 mL / min; eluent = EtOAc-hexane, 1:99 over 10 minutes, then 1:99 to 1: 3 over 40 minutes). Chromatography was repeated as above to give 2- (3-tert-butyl-isoxazol-5-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo as a white solid. [4,5-c] -pyridine was produced. Mass spectrum (LCMS, APCI pos.): Calculated for C ₂₁ H ₁₉ N ₄ O ₂ F ₃ : 417.1 (M + H); found: 417.1.

Step E: 2- (3-tert-butyl-isoxazol-5-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] -pyridine sodium salt 2- (3-tert-butyl-isoxazol-5-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine (67.3 mg, 0 .162 mmol, prepared as described above in Step D) in MeOH (5 mL) was treated with NaOMe (323 μL, 0.162 mmol, 0.5 M MeOH solution) and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give 2- (3-tert-butyl-isoxazol-5-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4 as an off-white solid. , 5-c] -pyridine sodium salt. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.66 (d, J = 7.8 Hz, 1H), 7.49-7.57 (m, 2H), 7.38-7.45 (m , 1H), 7.13 (s, 1H), 6.79 (s, 1H), 3.97 (s, 3H), 1.30 (s, 9H). Mass spectrum (LCMS, APCI pos.): Calculated for C ₂₁ H ₁₉ N ₄ O ₂ F ₃ : 417.1 (M + H); found: 417.1.

(Example 6)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5- c] Pyridine sodium salt (Compound # 9)

Step A: 5-tert-Butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-methoxy-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridine-4- Yl] -amido 2-methoxy-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-ylamine (162 mg, 0.517 mmol, prepared as described in Step B of Example 5 above) Was treated with NaH (62.1 mg, 1.55 mmol, 60% dispersion in oil) at room temperature and the mixture was allowed to stir at room temperature for 1 h. At the same time, a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (168 mg, 0.776 mmol, prepared as described in Example B above) in anhydrous DCM (10 mL) was added. Treated with oxalyl chloride (67.7 μL, 0.776 mmol) and DMF (2 drops) and the mixture was stirred at room temperature for 1 hour. Volatile components were removed under reduced pressure and the residue was taken up in anhydrous THF (6 mL). The acid chloride solution prepared as above was added to the sodium anilide solution and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted twice with EtOAc (25 mL). The residue was purified on a 12 g SEPRA Si 50 SPE column (flow rate = 15 mL / min; eluent = EtOAc-hexane, 1:99 over 10 minutes, then 1:99 to 3:17 over 40 minutes). However, as a white solid, 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-methoxy-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridine- 4-yl] -amide was produced. Mass spectrum (. LCMS, APCI pos): Calculated for _{C 22 H 21 N 5 O 4} ClF 3: 512.1 (M + H); Found: 512.1.

Step B: 2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4 , 5-c] pyridine 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-methoxy-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridine A solution of -4-yl] -amide (149 mg, 0.291 mmol, prepared as described above in Step A) in AcOH (10 mL) was treated with iron powder (81.3 mg, 1.46 mmol) and the resulting mixture Was heated to 100 ° C. over 1.5 hours. The cooled mixture was concentrated under reduced pressure, taken up in saturated aqueous NaHCO ₃ (50 mL) and extracted twice with EtOAc (40 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 12 g SEPRA Si 50 SPE column (flow rate = 15 mL / min; eluent = EtOAc-hexane, 1:99 over 10 minutes, then 1:99 to 1: 4 over 40 minutes). However, 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo as a white solid This gave [4,5-c] pyridine. Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₂ H ₂₁ N ₅ OClF ₃ : 464.1 (M + H); found: 464.2.

Step C: 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4 , 5-c] pyridine sodium salt 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl)- A solution of 3H-imidazo [4,5-c] pyridine (122 mg, 0.263 mmol, prepared as described in Step B above) in MeOH (6 mL) was treated with NaOMe (526 μL, 0.263 mmol) to obtain The mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure to give 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoromethyl) as a white solid. -Phenyl) -3H-imidazo [4,5-c] pyridine sodium salt was produced. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.77 (d, J = 7.8 Hz, 1H), 7.60-7.66 (m, 2H), 7.49-7.56 (m , 1H), 7.26 (s, 1H), 4.08 (s, 3H), 3.88 (s, 3H), 1.44 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₂ H ₂₁ N ₅ OClF ₃ : 464.1 (M + H); found: 464.2.

  Following the procedures described in Example 6 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 7)
2- (3-tert-butyl-isoxazol-5-yl) -7-trifluoromethyl-5- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b] pyridine (compound # 10 )

Step A: (6-Chloro-4-trifluoromethyl-pyridin-2-yl)-(4-methoxy-benzyl) -amine 2,6-dichloro-4-trifluoromethyl-pyridine (5.04 g, 23. 3 mmol) in pyridine (10 mL) was treated with 4-methoxybenzylamine (9.19 mL, 70.0 mmol) and heated to 110 ° C. for 26 hours. The mixture was cooled and pyridine (8 mL) was removed under reduced pressure. The remaining material was diluted with water (50 mL) and extracted twice with EtOAc (75 mL and 50 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 115 g SEPRA Si 35 SPE column (flow rate = 35 mL / min; eluent = EtOAc-hexane, 1:99 over 15 minutes, then from 1:99 to 1: 9 over 40 minutes, 2 1: 9 over minutes, then 1: 9 to 1: 4 over 20 minutes) to give (6-chloro-4-trifluoromethyl-pyridin-2-yl)-(4-methoxy- (Benzyl) -amine was produced and allowed to set to solidify. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.26 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.77 (s, 1H) , 6.44 (s, 1H), 5.21 (br.s., 1H), 4.44 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H). Mass spectrum (LCMS, ESI pos.): Calculated for C ₁₄ H ₁₂ N ₂ OClF ₃ : 317.1 (M + H); found: 317.1.

Step B: (4-Methoxy-benzyl)-[4-trifluoromethyl-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amine (6-chloro-4-trifluoromethyl-pyridine -2-yl)-(4-methoxy-benzyl) -amine (7.26 g, 22.9 mmol, prepared as described above in Step A) in DME (100 mL) / water (50 mL) was added 2-trifluoro Treated with methylphenylboronic acid (5.66 g, 29.8 mmol) and Cs ₂ CO ₃ (11.2 g, 34.4 mmol). The resulting mixture was degassed via heating under a stream of Ar. Cl ₂ Pd (dppf) · DCM (1.13 g, 1.38 mmol) was added and the mixture was heated to 80 ° C. for 4 hours. The cooled mixture was diluted with water (100 mL) and extracted twice with EtOAc (150 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 115 g SEPRA Si 35 SPE column (flow rate = 30 mL / min; eluent = EtOAc-hexane, 1:99 over 10 minutes, then 1:99 to 1: 4 over 40 minutes). However, (4-methoxy-benzyl)-[4-trifluoromethyl-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amine was produced as a yellow oil, which was allowed to stand to solidify. I let you. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.76 (d, J = 7.8 Hz, 1H), 7.57 to 7.63 (m, 1H), 7.47 to 7.55 (m, 2H), 7.27 (d, J = 8.6 Hz, 2H), 6.85 to 6.91 (m, 3H), 6.57 (s, 1H), 5.11 (t, J = 5. 2 Hz, 1H), 4.48 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H). Mass spectrum (LCMS, APCI pos.): Calculated for C ₂₁ H ₁₆ N ₂ OF ₆ : 427.1 (M + H); found: 427.2.

Step C: 4-trifluoromethyl-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine (4-methoxy-benzyl)-[4-trifluoromethyl-6- (2-trifluoromethyl- Phenyl) -pyridin-2-yl] -amine (1.00 g, 2.34 mmol, prepared as described above in Step B) in MeOH (20 mL) is added, the flask is flushed thoroughly with Ar and Pd / C (500 mg, 0.235 mmol, 5% on carbon) was added and the flask was flushed thoroughly with Ar and attached to a H ₂ balloon. The resulting mixture was stirred at room temperature for 4 hours. The balloon was removed, the flask was again flushed with Ar, the mixture was filtered through diatomaceous earth, and the filter cake was thoroughly washed with MeOH. The filtrate was concentrated under reduced pressure to yield 4-trifluoromethyl-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine as a tan solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.81 (d, J = 7.6 Hz, 1H), 7.64-7.76 (m, 2H), 7.59 (d, J = 7. 1 Hz, 1H), 7.25 (s, 1H), 6.79 (s, 1H), 3.22 (br.s., 4H).

Step D: 3-Nitro-4-trifluoromethyl-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine Sulfuric acid (10 mL ) And cooled to 0 ° C. 4-trifluoromethyl-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine (720 mg, 2.35 mmol, prepared as described in Step C above) with an internal temperature not exceeding 5 ° C. As such, it was added in small portions. The resulting mixture was stirred at 0 ° C. for 1 hour. Nitric acid (106 μL, 2.35 mmol) was added slowly to keep the internal temperature below 10 ° C. The mixture was stirred at 0 ° C. for a further 2 hours, poured onto ice water (100 mL), treated with 6M aqueous NaOH to pH 10 and extracted twice with EtOAc (100 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 24 g SEPRA Si 50 SPE column (flow rate = 20 mL / min; eluent = EtOAc-hexane, 1:99 over 10 minutes, then 1:99 to 1: 3 over 40 minutes). Thus, 3-nitro-4-trifluoromethyl-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine was produced as a bright yellow solid. Mass spectrum (LCMS, APCI pos.): Calculated for C ₁₃ H ₇ N ₃ O ₂ F ₆ : 352.0 (M + H); found: 352.0.

Step E: 3-tert-butyl-isoxazole-5-carboxylic acid [3-nitro-4-trifluoromethyl-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amide 3-nitro A solution of -4-trifluoromethyl-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine (64.0 mg, 0.182 mmol, prepared as described in Step D above) in THF (10 mL) was added. Treated with NaH (21.9 mg, 0.547 mmol, 60% dispersion in oil) and the resulting mixture was allowed to stir at room temperature for 1 hour. At the same time, a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (40.1 mg, 0.237 mmol, prepared as described in Example I above) in anhydrous DCM (10 mL) was added to oxalyl chloride (20.7 μL, 0.237 mmol) and DMF (2 drops) and the resulting mixture was stirred at room temperature for 1 hour. Volatile components were removed under reduced pressure and the residue was taken up in anhydrous THF (6 mL). The acid chloride solution prepared as above was added to the sodium anilide solution and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted twice with EtOAc (25 mL). The residue was purified on a 12 g SEPRA Si50 SPE column (flow rate = 15 mL / min; eluent = EtOAc-hexane, 1:99 over 10 minutes, then 1:99 to 1: 4 over 40 minutes). This gave 3-tert-butyl-isoxazole-5-carboxylic acid [3-nitro-4-trifluoromethyl-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amide as an off-white solid. . Mass spectrum (LCMS, APCI pos.): Calculated for C ₂₁ H ₁₆ N ₄ O ₄ F ₆ : 503.1 (M + H); found: 503.2.

Step F: 2- (3-tert-butyl-isoxazol-5-yl) -7-trifluoromethyl-5- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b] pyridine 3 -Tert-Butyl-isoxazole-5-carboxylic acid [3-nitro-4-trifluoromethyl-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amide (14.6 mg, 0. A solution of 029 mmol, prepared as described in Step E above) in AcOH (3 mL) with iron powder (8.12 mg, 0.145 mmol), and the resulting mixture was stirred at 100 ° C. for 2 h, Concentrated under. The residue was taken up in saturated aqueous NaHCO ₃ (30 mL) and extracted twice with EtOAc (25 mL). The combined organic extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 4 g SEPRA Si 50 SPE column (flow rate = 10 mL / min; eluent = EtOAc-hexane, 1:99 over 10 minutes, then 1:99 to 1: 4 over 40 minutes). However, 2- (3-tert-butyl-isoxazol-5-yl) -7-trifluoromethyl-5- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b] as a white solid This gave pyridine. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.77 (d, J = 7.6 Hz, 1H), 7.63-7.69 (m, 1H), 7.58-7.62 (m , 2H), 7.52 to 7.58 (m, 1H), 7.26 (s, 1H), 1.33 (s, 9H). Mass spectrum (LCMS, APCI pos.): Calculated for C ₂₁ H ₁₆ N ₄ OF ₆ : 455.1 (M + H); found: 455.1.

  Following the procedures described in Example 7 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 8)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b] pyrazine ( Compound # 95)

Step A: 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [5-bromo-3- (4-methoxy-benzylamino) -pyrazin-2-yl] -amide 3 60% NaH (120 mg, 3.00 mmol) was added in portions to a solution of, 5-dibromo-pyrazin-2-ylamine (252 mg, 1.00 mmol) in DME (10 mL). The resulting mixture was stirred at room temperature for 30 minutes, then 5-tert-butyl-4-chloride-2-methyl-2H-pyrazole-3-carbonyl chloride (234 mg, 1.00 mmol, of Example 1). Prepared as described in Step C). The resulting mixture was stirred at room temperature for 2 hours and treated with saturated NH ₄ Cl (20 mL) followed by EtOAc (20 mL). The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was dissolved in 1,4-dioxane (10 mL) and treated with 4-methoxybenzylamine (0.650 mL, 5.00 mmol). The resulting mixture was stirred at 65 ° C. for 2 hours. The resulting mixture was allowed to cool to room temperature and then treated with water (10 mL) and EtOAc (20 mL). The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was purified on silica (0: 100-50: 50 EtOAc: hexanes) to give 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [5 -Bromo-3- (4-methoxy-benzylamino) -pyrazin-2-yl] -amide was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.77 (br.s., 1H), 7.70 (s, 1H), 7.34 (d, J = 8.6 Hz, 2H), 6. 88 (d, J = 8.6 Hz, 2H), 6.28-6.36 (m, 1H), 4.59 (d, J = 5.1 Hz, 2H), 4.08 (s, 3H), 3.80 (s, 3H), 1.40 (s, 9H).

Step B: 5-tert-Butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3- (4-methoxy-benzylamino) -5- (2-trifluoromethyl-phenyl) -pyrazine -2-yl] -amide 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [5-bromo-3- (4-methoxy-benzylamino) -pyrazin-2-yl ] To a solution of -amide (87 mg, 0.17 mmol), 2-trifluoromethyl-phenylboronic acid (36 mg, 0.19 mmol) in DMF (0.5 mL) / toluene (2 mL) / water (2 mL), K ₂ CO ₃ (33 mg, 0.23 mmol) was added. The resulting solution was placed under Ar and (dppf) PdCl ₂ · DCM (14 mg, 0.02 mmol) was added. The resulting mixture was stirred at 100 ° C. overnight. The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was purified on silica (20:80 to 100: 0 EtOAc: hexanes) to give 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3 This gave-(4-methoxy-benzylamino) -5- (2-trifluoromethyl-phenyl) -pyrazin-2-yl] -amide. Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₈ H ₂₈ ClF ₃ N ₆ O: 573.1 (M + H); found: 573.3.

Step C: 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b Pyrazine 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [5-bromo-3- (4-methoxy-benzylamino) -pyrazin-2-yl] -amide (28 mg , 0.04 mmol, prepared as described in the previous step) in TFA (3.5 mL) was stirred at 65 ° C. for 3 h. The resulting mixture was allowed to cool to room temperature, TFA was removed under reduced pressure, and the resulting residue was dissolved in EtOAc (10 mL) and washed with saturated NaHCO ₃ (20 mL). The EtOAc layer was separated, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting residue was dissolved in HOAc (3.5 mL) and stirred at 100 ° C. overnight. The resulting mixture was allowed to cool to room temperature and HOAc was removed under reduced pressure. The resulting residue was dissolved in EtOAc (10 mL) and washed with saturated NaHCO ₃ (10 mL). The EtOAc layer was separated, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting residue was purified on silica (0: 100-50: 50 EtOAc-hexane) to give 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl). ) -6- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b] pyrazine. ¹ H-NMR (CD ₃ OD) δ: 8.53 to 8.57 (brs, 1H), 7.82 to 7.86 (m, 1H), 7.68 to 7.74 (m, 1H) 7.61-7.67 (m, 1H), 7.57-7.60 (m, 1H), 4.19 (s, 3H), 1.43 (s, 9H). Mass spectrum (. LCMS, ESI pos): C 20 H 18 ClF Calculated _{3 N 6: 435.1 (M +} H); Found: 435.1.

  Following the procedures described in Example 8 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

Example 9
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -7-methoxy-5- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5- b] Pyridine (Compound # 62)

Step A: 4-Methoxy-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine 4-chloro-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridine- To a solution of 2-ylamine (317 mg, 0.998 mmol, prepared as described in Example 1) in MeOH (5 mL) was added NaOMe (1.99 mL, 0.998 mmol, 0.5 M MeOH solution). The resulting mixture was stirred at 70 ° C. overnight. The reaction mixture was then diluted with water (20 mL) and extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried (MgSO ₄ ) and concentrated. The resulting residue was purified on silica (0: 100-50: 50 EtOAc-hexane) to give 4-methoxy-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridine-2- This gave ilamine. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.78 (d, J = 7.8 Hz, 1H), 7.61-7.67 (m, 1H), 7.54-7.60 (m, 1H), 7.50 (d, J = 7.6 Hz, 1H), 6.46 (s, 1H), 6.27 (br.s., 2H), 3.97 (s, 3H).

Step B: 2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -7-methoxy-5- (2-trifluoromethyl-phenyl) -1H-imidazo [4 , 5-b] pyridine Prepare the title compound from 4-methoxy-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine according to the procedure described in steps C and D of Example 1. did. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: ¹ H-NMR (CD ₃ OD) δ: 7.82 (d, J = 7.3 Hz, 1 H), 7.66 to 7.73 (m, 1 H) 7.56-7.66 (m, 2H), 6.99 (s, 1H), 4.12 (s, 3H), 4.02 (s, 3H), 1.43 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₂₂ H ₂₁ ClF ₃ N ₅ O: 464.1 (M + H), found: 464.3.

  Following the procedures described in Example 9 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 10)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -5- (2-trifluoromethoxy-phenyl) -1H-imidazo [4,5-b] pyrazine ( Compound # 94)

Step A: 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (3-amino-5-bromo-pyrazin-2-yl) -amide 5-bromo-pyrazine-2, To a mixed solution of 3-diamine (250 mg, 1.32 mmol) in 1: 1 DMF / DCM (8 mL) was slowly added NaH (159 mg, 3.97 mmol, 60% dispersion in mineral oil). After stirring at room temperature for 1 hour, the resulting mixture was cooled to 0 ° C. Solid 5-tert-butyl-4-chloride-2-methyl-2H-pyrazole-3-carbonyl chloride (373 mg, 1.59 mmol, prepared as described in Example 1, Step C) was added slowly. The resulting mixture was warmed to room temperature and then stirred for 18 hours. The resulting mixture was treated with 50 mL of EtOAc and washed with aqueous saturated NH ₄ Cl (20 mL), H ₂ O (2 × 10 mL) and brine (10 mL). After drying over Na ₂ SO ₄ , the resulting solution was concentrated under reduced pressure and the residue was purified by flash chromatography on silica (0: 100-20: 80 EtOAc / hexanes). This gave 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (3-amino-5-bromo-pyrazin-2-yl) -amide as a light brown solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.88 (s, 1H), 8.12 (s, 1H), 5.34 (br.s., 2H), 4.14 (s, 3H) , 1.42 (s, 9H). Mass spectrum (LCMs, ESI pos.) Measured value for C ₁₃ H ₁₆ BrClN ₆ O: 387.0 (M + H), measured value: 387.0.

Step B: 2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -5- (2-trifluoromethoxy-phenyl) -1H-imidazo [4,5-b Pyrazine 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (3-amino-5-bromo-pyrazin-2-yl) -amide (45.0 mg, 0.116 mmol, Prepared as described in previous step), 2-trifluoromethoxy-phenyl-boronic acid (28.7 mg, 0.139 mmol), Cs ₂ CO ₃ (95 mg, 0.29 mmol) and Pd (dppf) ₂ · DCM To a 1,4-dioxane (3 mL) solution of a mixture of (9.5 mg, 0.012 mmol) was added water (1.5 mL). After stirring at 100 ° C. for 16 h, the resulting mixture was cooled to room temperature, treated with EtOAc (50 mL), washed with H ₂ O (20 mL), brine (20 mL), and Na ₂ SO ₄ Dried. The solvent was removed under reduced pressure and the residue was subjected to flash chromatography on silica gel (0: 100-35: 65 EtOAc-hexane) to give 2- (5-tert-butyl-4-) as a light yellow solid. Chloro-2-methyl-2H-pyrazol-3-yl) -5- (2-trifluoromethoxy-phenyl) -1H-imidazo [4,5-b] pyrazine was produced. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.79 (s, 1H), 7.87 to 7.94 (m, 1H), 7.45 to 7.64 (m, 3H), 4. 14 (s, 3H), 1.44 (s, 9H). Mass spectrum (. LCMs, ESI pos) C 20 H 18 ClF 3 N 6 O Calculated: 451.1 (M + H), Found: 451.1.

  Following the procedures described in Example 10 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 11)
2- [2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c ] Pyridin-4-yloxy] -ethanol (Compound # 57)

Step A: 2- (4-Amino-6-chloro-3-nitro-pyridin-2-yloxy) -ethanol 60% sodium hydride mineral oil dispersion (769 mg, 19.2 mmol) in ethylene glycol (10 mL) mixed solution 2,6-dichloro-3-nitro-pyridin-4-ylamine (2.00 g, 9.62 mmol) was added slowly over 5 minutes. After stirring at room temperature for 16 hours, the resulting mixture was treated with saturated NH ₄ Cl (20 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with H ₂ O (2 × 50 mL), brine (50 mL) and then dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the resulting residue was triturated with hexane. 2- (4-Amino-6-chloro-3-nitro-pyridin-2-yloxy) -ethanol was obtained (by filtration) as a light yellow solid and washed with hexane. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 6.50 (s, 1H), 4.37 to 4.50 (m, 2H), 3.80 to 3.93 (m, 2H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₇ H ₈ ClN ₃ O ₄ : 234.0 (M + H), found: 234.0.

Step B: 2- [2- (tert-Butyl-dimethyl-silanyloxy) -ethoxy] -6-chloro-3-nitro-pyridin-4-ylamine 2- (4-amino-6-chloro-3-nitro-pyridine 2-yloxy) -ethanol (4.40 g, 18.8 mmol, prepared as described in previous step) and tert-butyl-chloro-dimethyl-silane (3.12 g, 20.7 mmol) in DCM ( To the 50 mL) solution was added imidazole (1.80 g, 26.4 mmol). After stirring at room temperature for 2 hours, the resulting mixture was treated with saturated NH ₄ Cl (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with H ₂ O (3 × 50 mL), brine (50 mL) and then dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (0: 100-20: 80 EtOAc / hexanes) to give 2- [2- (tert-butyl- Dimethyl-silanyloxy) -ethoxy] -6-chloro-3-nitro-pyridin-4-ylamine was produced. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.35 (s, 1H), 6.17 (br.s., 2H), 4.49 (t, J = 5.1 Hz, 2H), 3. 96 (t, J = 5.1 Hz, 2H), 0.88 (s, 9H), 0.08 (s, 6H).

Step C: 2- [2- (tert-Butyl-dimethyl-silanyloxy) -ethoxy] -3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-ylamine 2- [2- (tert- Butyl-dimethyl-silanyloxy) -ethoxy] -6-chloro-3-nitro-pyridin-4-ylamine (1.20 g, 3.45 mmol, prepared as described in the previous step) and 2-trifluoromethyl-phenyl - boronic acid (786 mg, 4.14 mmol) and _{Cs 2 CO 3 (2.81g, 8.62mmol} ) and _{Pd (dppf) 2 · DCM (} 282mg, 0.345mmol) in a mixture of 1,4-dioxane (12 mL) Water (5 mL) was added to the solution. The resulting mixture was stirred at 110 ° C. for 2 hours under microwave irradiation and then cooled to room temperature. The resulting mixture was treated with EtOAc (50 mL), then washed with H ₂ O and brine and dried (Na ₂ SO ₄ ). After removal of the solvent under reduced pressure, the residue was subjected to flash chromatography on silica gel (5: 95-40: 60 EtOAc-hexane) to give 2- [2- (tert-butyl- Dimethyl-silanyloxy) -ethoxy] -3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-ylamine was produced. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.76 (d, J = 7.8 Hz, 1H), 7.51 to 7.65 (m, 2H), 7.46 (d, J = 7. 3 Hz, 1H), 6.41 (s, 1H), 6.08 (br.s., 2H), 4.50 (t, J = 5.3 Hz, 2H), 3.95 (t, J = 5) .3 Hz, 2H), 0.89 (s, 9H), 0.07 (s, 6H). Mass spectrum (. LCMs, ESI pos) Calcd for _{C 20 H 26 F 3 N 3} O 4 Si: 458.1 (M + H), Found: 458.0.

Step D: 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2- [2- (tert-butyl-dimethyl-silanyloxy) -ethoxy] -3-nitro-6 (2-Trifluoromethyl-phenyl) -pyridin-4-yl] -amide 60% of a dispersion of sodium hydride in mineral oil (120 mg, 3.00 mmol) in THF (10 mL) at 0 ° C. 2- (tert-Butyl-dimethyl-silanyloxy) -ethoxy] -3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-ylamine (458 mg, 1.00 mmol, as described in the previous step. Was slowly added. The resulting mixture was warmed to room temperature and then stirred for 1 h under Ar. 5-tert-Butyl-4-chloride-2-methyl-2H-pyrazole-3-carbonyl chloride (259 mg, 1.10 mmol, prepared as described in Example 1, Step C) was added and the resulting mixture Was stirred under Ar for 3 hours. After quenching with saturated aqueous NH ₄ Cl (5 mL), the mixture was treated with EtOAc (100 mL), washed with H ₂ O, brine, and dried over Na ₂ SO ₄ . After removal of the solvent under reduced pressure, the residue was subjected to flash chromatography on silica gel (0: 100-10: 90 EtOAc / hexanes) to give 5-tert-butyl-4-chloro-2 as a white solid. -Methyl-2H-pyrazole-3-carboxylic acid [2- [2- (tert-butyl-dimethyl-silanyloxy) -ethoxy] -3-nitro-6- (2-trifluoromethyl-phenyl) -pyridine-4- Yl] -amide. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 10.10 (s, 1H), 8.33 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.62 to 7.70 (m, 1H), 7.52 to 7.62 (m, 2H), 4.51 to 4.61 (m, 2H), 4.11 (s, 3H), 3.94 to 4. 01 (m, 2H), 1.42 (s, 9H), 0.89 (s, 9H), 0.07 (s, 6H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₂₉ H ₃₇ ClF ₃ N ₅ O ₅ Si: 656.2 (M + H), found: 656.2.

Step E: 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4- [2- (tert-butyl-dimethyl-silanyloxy) -ethoxy] -6- ( 2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2- [2- (tert -Butyl-dimethyl-silanyloxy) -ethoxy] -3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-yl] -amide (428 mg, 0.650 mmol, as described in the previous step. Prepared) and iron powder (291 mg, 5.22 mmol) in a 1: 1 AcOH / EtOH (7 mL) solution was stirred at 100 ° C. under Ar for 1 h. It was. After cooling to room temperature, the mixture was treated with EtOAc (20 mL) and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (0: 100-10: 90 EtOAc / hexanes) to give 2- (5-tert-butyl-4 as a white solid. -Chloro-2-methyl-2H-pyrazol-3-yl) -4- [2- (tert-butyl-dimethyl-silanyloxy) -ethoxy] -6- (2-trifluoromethyl-phenyl) -3H-imidazo [ 4,5-c] pyridine was produced. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.81 (d, 1H), 7.65 to 7.71 (m, 1H), 7.55 to 7.62 (m, 2H), 7. 31 (s, 1H), 4.64 (t, J = 4.9 Hz, 2H), 4.02 to 4.10 (m, 5H), 1.44 (s, 9H), 0.86 (s, 9H), 0.06 (s, 6H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₂₉ H ₃₇ ClF ₃ N ₅ O ₂ Si: 608.2 (M + H), found: 608.3.

Step F: 2- [2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4 5-c] pyridin-4-yloxy] -ethanol 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4- [2- (tert-butyl-dimethyl-) Silanyloxy) -ethoxy] -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine (390 mg, 0.641 mmol, prepared as described in previous step) and tetrabutylammonium A solution of fluoride hydrate (914 mg, 3.21 mmol) in THF (10 mL) was stirred at 50 ° C. for 18 hours. After cooling to room temperature, the resulting mixture was treated with EtOAc (50 mL) and washed with H ₂ O (2 × 20 mL), brine (20 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (40: 60-60: 40 EtOAc / heptane) to give 2- [2- (5-tert-butyl-4-chloro-2--2-ethyl) as a white solid. This resulted in methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridin-4-yloxy] -ethanol. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.67 (dd, J = 7.3, 2.0 Hz, 1H), 7.48-7.56 (m, 2H), 7.39 (td , J = 6.7, 1.8 Hz, 2H), 4.64 to 4.68 (m, 2H), 4.05 (s, 3H), 3.97 to 4.02 (m, 2H), 1 .42 to 1.49 (m, 9H). Mass spectrum (. LCMs, ESI pos) C 23 H 23 ClF 3 N 5 O 2 Calculated: 492.2 (M + H), Found: 492.4.

  Following the procedures described in Example 11 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 12)
[2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine -4-yloxy] -acetic acid (Compound # 88)

Step A: [2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5- c] Pyridin-4-yloxy] -acetaldehyde 2- [2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) To a suspension of −3H-imidazo [4,5-c] pyridin-4-yloxy] -ethanol (230 mg, 0.466 mmol, prepared as described in Example 11, Step F) in DCM (10 mL) Dess-Martin periodinane (395 mg, 0.931 mmol) was added at ° C. The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched by adding 10% aqueous Na ₂ S ₂ O ₃ (20 mL). The resulting mixture was treated with EtOAc (50 mL) and washed with saturated NaHCO ₃ solution (20 mL), H ₂ O (20 mL) and brine (20 mL). After drying over Na ₂ SO ₄ , the resulting solution was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (20: 80-50: 50 EtOAc / hexanes). [2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5- c] gave pyridin-4-yloxy] -acetaldehyde. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.67 (dd, J = 7.5, 1.9 Hz, 1H), 7.49-7.54 (m, 2H), 7.35-7. 44 (m, J = 7.3, 7.3, 7.3, 7.3, 1.6 Hz, 2H), 5.07 (t, J = 4.9 Hz, 1H), 4.52 (dd, J = 4.8, 1.5 Hz, 2H), 4.04 (s, 3H), 1.45 (s, 9H). Mass spectrum (. LCMs, ESI pos) C 23 H 21 F 3 N 5 O 2 Calculated: 492.1 (M + H), Found: 492.1.

Step B: [2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5- c] Pyridin-4-yloxy] -acetic acid [2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) -3H -Imidazo [4,5-c] pyridin-4-yloxy] -acetaldehyde (30.0 mg, 0.0610 mmol, prepared as described in previous step) 5: 5: 2 tert-BuOH / 2-methyl- in a mixed solution of 2-butene / H ₂ O (1.2mL), was added sodium chlorite (11.6 mg, 0.128 mmol), then sodium dihydrogen phosphate (17.8 mg, 0.1 3mmol) was added. After stirring at room temperature for 16 hours, the resulting mixture was treated with 1N NaOH (2 mL) and concentrated under reduced pressure. The resulting residue was treated with H ₂ O (20 mL) and washed with EtOAc (2 × 10 mL). The aqueous phase was acidified to pH 5 by adding HOAc and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with H ₂ O (15 mL), brine (15 mL) and then dried over Na ₂ SO ₄ . When the solvent was removed under reduced pressure, [2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) was obtained as a light yellow solid. ) -3H-imidazo [4,5-c] pyridin-4-yloxy] -acetic acid. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.13 to 8.04 (m, 5H), 5.10 (s, 2H), 4.06 (s, 3H), 1.43 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₂₃ H ₂₁ ClF ₃ N ₅ O ₃ : 508.1 (M + H), found: 508.1.

  Following the procedures described in Example 12 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 13)
{2- [2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5- c] Pyridin-4-yloxy] -ethyl} -dimethyl-amine (Compound # 53)

[2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine -4-yloxy] -acetaldehyde (40.0 mg, 0.0813 mmol, prepared as described in Example 12, Step A) in a mixed solution of 30: 1 MeOH / AcOH (2 mL) with 2.0 M dimethylamine. Of THF (81.3 μL, 0.163 mmol) was added followed by sodium cyanoborohydride (10.2 mg, 0.163 mmol). After stirring at room temperature for 18 hours, the resulting mixture was treated with EtOAc (50 mL) and washed with saturated aqueous NH ₄ Cl (20 mL), H ₂ O (20 mL) and brine (20 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0: 100-10: 90 MeOH / DCM) to give {2- [2- (5-tert-butyl-4 as a light yellow solid). -Chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridin-4-yloxy] -ethyl} -dimethyl- An amine was produced. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.84 (d, J = 7.6 Hz, 1H), 7.67-7.75 (m, 1H), 7.58-7.66 (m , 2H), 7.37-7.43 (m, 1H), 4.80-4.86 (m, 2H), 4.03 (s, 3H), 3.47-3.55 (m, 2H) ), 2.88 (s, 6H), 1.45 (s, 9H). Mass spectrum (. LCMs, ESI pos) C 25 H 28 ClF 3 N 6 O Calculated: 521.2 (M + H), Found: 521.2.

  Following the procedures described in Example 13 above, the following representative compounds of the invention were prepared by substituting appropriately selected and substituted reagents, starting materials, and conditions that would be readily apparent to one skilled in the art.

(Example 14)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2,6-dichloro-phenyl) -4-methoxy-3H-imidazo [4,5- c] Pyridine sodium salt (Compound # 103)

Step A: 6- (2,6-Dichlorophenyl) -4-hydroxy-1H-pyridin-2-one NaH (400 mg, 10.0 mmol, 60% mineral oil dispersion) in a 100 mL round bottom flask equipped with a stir bar. Was then evacuated and backflushed with Ar. Anhydrous THF (30 mL) was added via syringe and methyl acetoacetate (1.08 mL, 10.0 mmol) was added dropwise to the stirred mixture via syringe. Once the solution is homogeneous, the mixture is cooled to −78 ° C. and n-BuLi (4.20 mL of 2.5 M hexane) is injected via a syringe at such a rate as to maintain the internal temperature below −70 ° C. Solution, 10.5 mmol) was added dropwise. The resulting mixture was stirred at −78 ° C. for 30 minutes and 2,6-dichlorobenzonitrile (1.72 g, 10.0 mmol) was added in one portion as a solid. The resulting solution was stirred at −78 ° C. so that the reaction was slowly warmed to room temperature overnight (about 16 hours).

The resulting mixture was then cooled in an ice bath and concentrated HCl was added dropwise at a rate that maintained the internal temperature below 5 ° C. to a pH of about 4. The resulting mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure.

Toluene was added to the residue and the resulting mixture was refluxed for 24 hours. The resulting mixture was then cooled to room temperature and the solid was isolated by filtration. The solid was washed with toluene (20 mL) and the residual solvent was removed under reduced pressure to yield 6- (2,6-dichlorophenyl) -4-hydroxy-1H-pyridin-2-one. ¹ H NMR (400 MHz, CD ₃ OD) δ: 7.50-7.56 (m, 2H), 7.43-7.49 (m, 1H), 5.99 (d, J = 2.2 Hz, 1H), 5.84 (d, J = 2.2 Hz, 1H).

Step B: 6- (2,6-Dichloro-phenyl) -4-hydroxy-3-nitro-1H-pyridin-2-one 6- (2,6-Dichlorophenyl) in an 8 mL vial with stir bar -4-Hydroxy-1H-pyridin-2-one (253 mg, 0.990 mmol, prepared as described in the previous step) was placed and AcOH (4 mL) was added. Concentrated HNO ₃ (0.540 mL, 12.0 mmol) was added via syringe, the vial was capped and stirred at 60 ° C. for 14 hours. The resulting mixture was cooled to room temperature and poured onto crushed ice (20 mL). The precipitate was separated by filtration and washed with H ₂ O (10 mL). The solid was air dried to yield 6- (2,6-dichloro-phenyl) -4-hydroxy-3-nitro-1H-pyridin-2-one as a yellow powder. The filtrate was extracted with EtOAc (3 × 10 mL) and the combined extracts were washed with H ₂ O (20 mL), dried over MgSO ₄ and filtered. Removal of the solvent under reduced pressure yielded an additional crop of 6- (2,6-dichloro-phenyl) -4-hydroxy-3-nitro-1H-pyridin-2-one. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.48-7.61 (m, 3H), 6.13 (s, 1H).

Step C: 2,4-Dichloro-6- (2,6-dichloro-phenyl) -3-nitro-pyridine 6- (2,6-Dichloro-phenyl) -4 in an 8 mL vial equipped with a stir bar - hydroxy-3-nitro--1H- pyridin-2-one place (208mg, 0.689mmol, prepared as described in the previous step) was added POCl ₃ and (4 mL). The resulting mixture was stirred at 100 ° C. for 24 hours, cooled to room temperature and poured onto crushed ice. This solid was isolated by filtration, dissolved in DCM (20 mL), dried over MgSO ₄ and filtered. The solvent was removed under reduced pressure and the resulting residue was chromatographed on a pre-packed 24-g SiO ₂ column eluting with 0: 1-1: 0 EtOAc / heptane to give 2, This gave 4-dichloro-6- (2,6-dichloro-phenyl) -3-nitro-pyridine. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.51 (s, 1H), 7.41-7.48 (m, 2H), 7.33-7.41 (m, 1H).

Step D: 2-chloro-6- (2,6-dichlorophenyl) -3-nitropyridin-4-ylamine 2,4-dichloro-6- (2,6-dichloro) in an 8 mL vial equipped with a stir bar -Phenyl) -3-nitro-pyridine (94.4 mg, 0.279 mmol, prepared as described in the previous step) was placed and anhydrous MeOH (2 mL) was added via syringe. The resulting solution was gently heated with a heat gun to dissolve the solid, and 7M NH ₃ in MeOH (2.00 mL, 14.0 mmol) was added via syringe. The resulting mixture was stirred at room temperature for 16 hours and the solvent was removed under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (TLC) developed on a 2000 μ SiO ₂ plate with 1: 4 EtOAc / heptane to give 2-chloro-6- (2,6-dichlorophenyl). This gave -3-nitropyridin-4-ylamine. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.33-7.45 (m, 2H), 7.27-7.33 (m, 1H), 6.68 (s, 1H), 5.86 (Br.s., 2H). _{LCMS (ESI): C 11 H} 6 ClN 3 O 2 Calculated: 318.0 (M + H); Found: 318.0.

Step E: 6- (2,6-Dichlorophenyl) -2-methoxy-3-nitropyridin-4-ylamine 2-chloro-6- (2,6-dichlorophenyl)-in an 8 mL vial equipped with a stir bar 3-Nitropyridin-4-ylamine (28.7 mg, 0.0901 mmol, prepared as described in the previous step) was placed and anhydrous MeOH (1 mL) was added via syringe. NaOMe (0.5 M MeOH solution (0.396 mL, 0.198 mmol)) was added to the stirred mixture and then stirred at 65 ° C. for 4 hours. The solvent was removed under reduced pressure and the resulting residue was chromatographed on a pre-packed 12 g SiO ₂ column eluting with 0: 1 to 2: 3 EtOAc / heptane to give 6- (2, 6-Dichlorophenyl) -2-methoxy-3-nitropyridin-4-ylamine was produced. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.37-7.41 (m, 2H), 7.25-7.30 (m, 1H), 6.35 (s, 1H), 6.15 (Br.s., 2H), 4.01 (s, 3H).

Step F: 2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2,6-dichloro-phenyl) -4-methoxy-3H-imidazo [4 , 5-c] pyridine According to the procedure described in Step C of Example 25, 6- (2,6-dichlorophenyl) -2-methoxy-3-nitropyridin-4-ylamine (24.2 mg, 0.0770 mmol, i.e. ) And 5-tert-butyl-4-chloride-2-methyl-2H-pyrazole-3-carbonyl chloride (18.1 mg, 0.0770 mmol, as described in Step C of Example 1). From 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2,6-dichloro-phenyl) -4-methoxy-3H -Imidazo [4,5-c] pyridine was prepared. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.47 to 7.53 (m, J = 8.3 Hz, 2H), 7.39 (dd, J = 8.8, 7.3 Hz, 1H) , 7.21 (s, 1H), 4.12 (s, 3H), 4.04 (s, 3H), 1.45 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₁ H ₂₀ Cl ₃ N ₅ O: 464.1 (M + H); found: 464.0.

Step G: 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2,6-dichloro-phenyl) -4-methoxy-3H-imidazo [4 , 5-c] pyridine sodium salt Following the procedure described in Step F of Example 1, 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2 , 6-dichlorophenyl) -4-methoxy-3H-imidazo [4,5-c] pyridine (11.6 mg, 0.0250 mmol, prepared as described in previous step) and 0.5 M NaOMe in MeOH ( 50.0 μL, 0.00.0250 mmol) as a white foam 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2,6-dichloro) -Fe ) -4- methoxy -3H- imidazo [4,5-c] pyridine sodium salt was prepared. ¹ H-NMR (400 MHz, d ₆ -DMSO) δ: 7.51 to 7.55 (m, 2H), 7.39 (dd, J = 8.7, 7.5 Hz, 1H), 7.00 ( s, 1H), 4.02 (s, 3H), 3.89 (s, 3H), 1.39 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₁ H ₂₀ Cl ₃ N ₅ O: 464.1 (M + H); found: 464.0.

(Example 15)
2- (5-tert-butyl-4-methoxy-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5- c] pyridine methanesulfonate (compound # 79); and 2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) ) -3H-imidazo [4,5-c] pyridine methanesulfonate (Compound # 80)

Step A: 2- (5-tert-butyl-4-methoxy-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4 , 5-c] pyridine and 2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4 , 5-c] pyridine 5-tert-butyl-4-methoxy-2-methyl-2H-pyrazole-3-carboxylic acid (49.7 mg, 0.234 mmol, prepared as described in Example E) in DCM ( 2 mL) and DMF (10 μL) was added. Oxalyl chloride (30.6 μL, 0.351 mmol) was added via syringe and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in anhydrous THF (3 mL).

Of 2-methoxy-3-nitro-6- (2-trifluoromethyl-phenyl) -4-pyridin-4-ylamine (73.3 mg, 0.234 mmol, prepared as described in Example 5, Step B) Anhydrous THF (3 mL) solution was cooled to 0 ° C. in an ice bath under Ar and treated with NaH (28.1 mg of 60% mineral oil dispersion, 0.702 mmol). A solution of the acid chloride in THF (prepared as described above) was then added dropwise to the stirred mixture. The resulting mixture was then stirred at 0 ° C. for 1 hour, then poured onto ice (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over MgSO ₄ , filtered and the solvent removed under reduced pressure.

The resulting residue was dissolved in ice AcOH (2 mL) and Fe powder (65.3 mg, 1.17 mmol) was added. The resulting mixture was stirred at 100 ° C. for 1 h and the cooled mixture was poured onto ice (20 mL). The resulting aqueous solution was extracted with EtOAc (3 × 20 mL) and the combined extracts were washed with 1M LiOH (20 mL) and brine (20 mL). The organic layer was dried over MgSO ₄ and filtered. The solvent was removed under reduced pressure and the resulting residue was chromatographed on a 24 g pre-packed SiO ₂ column eluting with 0: 1 to 4: 1 EtOAc / hexane to give 2- (5-tert -Butyl-4-methoxy-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoro-methyl-phenyl) -3H-imidazo [4,5-c] pyridine It was. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.81 (d, J = 7.8 Hz, 1H), 7.65 to 7.72 (m, 1H), 7.55 to 7.63 (m , 2H), 7.31 (s, 1H), 4.12 (s, 3H), 4.03 (s, 3H), 3.62 (s, 3H), 1.39 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₃ H ₂₄ F ₃ N ₅ O ₂ : 460.2 (M + H); found: 460.2.

2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine Isolated. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.81 (d, J = 7.8 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.54 to 7.64 (M, 2H), 7.26 (br.s., 1H), 6.79 (br.s., 1H), 4.26 (s, 3H), 4.12 (s, 3H), 1. 36 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₂ H ₂₂ F ₃ N ₅ O: 430.2 (M + H); found: 430.2.

Step B: 2- (5-tert-butyl-4-methoxy-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoro-methyl-phenyl) -3H-imidazo [ 4,5-c] pyridine methanesulfonate 2- (5-tert-butyl-4-methoxy-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoro-methyl) -Phenyl) -3H-imidazo [4,5-c] pyridine (54.4 mg, 0.118 mmol, prepared in Step A above) was dissolved in EtOAc (1 mL) and 0.5 M MsOH in EtOAc (237 μL, 0.118 mmol) was added. The resulting solution was mixed well and the solvent was removed under reduced pressure to give 2- (5-tert-butyl-4-methoxy-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6. This yielded-(2-trifluoro-methyl-phenyl) -3H-imidazo [4,5-c] pyridine methanesulfonate. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.82 to 7.90 (m, 1H), 7.72 to 7.80 (m, 1H), 7.61 to 7.69 (m, 2H), 7.32 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.61 (s, 3H), 2.34 (s, 3H), 1. 35 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₃ H ₂₄ F ₃ N ₅ O ₂ : 460.2 (M + H); found: 460.2.

Step C: 2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c Pyridine methanesulfonate 2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4 5-c] pyridine (9.2 mg, 0.021 mmol, prepared as in Step A) was dissolved in EtOAc (1 mL) and 0.5 M MsOH in EtOAc (41 μL, 0.021 mmol) was added. The resulting solution was mixed well and the solvent was removed under reduced pressure to give 2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -4-methoxy-6- (2- Trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine methanesulfonate was produced. ¹ H-NMR (400 MHz, acetone-d ₆ ) δ: 7.88 (d, J = 8.1 Hz, 1H), 7.74-7.80 (m, 1H), 7.66-7.73 ( m, 2H), 7.62 (s, 1H), 7.17 (s, 1H), 4.36 (s, 3H), 4.33 (s, 3H), 2.80 (s, 3H), 1.33 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₂ H ₂₂ F ₃ N ₅ O: 430.2 (M + H); found: 430.2.

(Example 16)
3-tert-butyl-5- [4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridin-2-yl] -1-methyl-1H-pyrazole- 4-carbonitrile hydrochloride (compound # 75)

Step A: 5-Nitro-2- (2-trifluoromethyl - phenyl) - pyridin-4-ylamine 2-Bromo-5-nitro-4-amine (561 mg, 2.57 mmol) and Cs ₂ CO ₃ (2 .52 g, 7.72 mmol), (dppf) PdCl ₂ · DCM (113 mg, 0.154 mmol) and 2- (trifluoromethyl) phenylboronic acid (636 mg, 3.35 mmol) were combined, flushed with Ar, anhydrous DME (24 mL) was added. H ₂ O (8 mL) was added via syringe and the resulting mixture was stirred at 85 ° C. for 18 hours. The resulting mixture was cooled to room temperature, diluted with EtOAc (30 mL), and the resulting solution was washed with brine (30 mL). The aqueous phase was extracted with EtOAc (3 × 25 mL) and the combined organic extracts were dried over MgSO ₄ and filtered. The solvent was removed under reduced pressure and the resulting residue was chromatographed on a pre-packed 40 g SiO ₂ column eluting with 0: 1 to 2: 3 EtOAc / hexane to give 5-nitro-2. This gave-(2-trifluoromethyl-phenyl) -pyridin-4-ylamine. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 9.17 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.1 Hz, 1H) 7.49 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.00 (br.s., 2H), 6.71 (s, 1H) ). Mass spectrum (LCMS, ESI pos.): Calculated for C ₁₂ H ₈ F ₃ N ₃ O ₂ : 284.1 (M + H); found: 284.1.

Step B: 2-Chloro-6- (2-trifluoromethyl-phenyl) -pyridin-3,4-diamine 5-nitro-2- (2-trifluoromethyl-phenyl) -pyridin-4-ylamine (749 mg, 2.65 mmol, prepared as in the previous step) was dissolved in concentrated HCl (12 mL) and heated to 90 ° C. and SnCl ₂ .2H ₂ O (2.98 g, 13.2 mmol) was added portion-wise to this stirred mixture. And the resulting mixture was stirred at 90 ° C. for 1 hour. After complete addition, the resulting mixture was cooled to 0 ° C. with an ice bath, treated with 6M aqueous NaOH (30 mL), and then extracted with DCM (3 × 40 mL). The combined extracts were dried over MgSO ₄ and filtered. The solvent was removed under reduced pressure and the resulting residue was chromatographed on a pre-packed 40 g SiO ₂ column eluting with 0: 1 to 3: 2 EtOAc / hexane to give 2-chloro-6. This gave-(2-trifluoromethyl-phenyl) -pyridine-3,4-diamine. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.67 (d, J = 7.8 Hz, 1H), 7.47 to 7.55 (m, 1H), 7.37 to 7.46 (m, 2H), 6.57 (s, 1H), 4.09 (br s., 2H), 3.74 (br.s., 2H).

Step C: 3-tert-butyl-5- [4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridin-2-yl] -1-methyl-1H -Pyrazole-4-carbonitrile 3-tert-butyl-4-cyanopyrazole-5-carboxylic acid (92.6 mg, 0.447 mmol, prepared as in Example C) was dissolved in DCM (2 mL) and DMF ( 10 μL) and oxalyl chloride (53.1 μL, 0.609 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The residue was dissolved in DCM (2 mL).

2-Chloro-6- (2-trifluoromethyl-phenyl) -pyridine-3,4-diamine (117 mg, 0.406 mmol, prepared as in Step B above) was dissolved in DCM (3 mL) and DIEA (141 μL). , 0.812 mmol). The acid chloride solution was added dropwise to the stirred mixture, which was then stirred at room temperature for an additional 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in POCl ₃ (1.5 mL). The resulting solution was stirred at 100 ° C. for 16 hours, then cooled to room temperature and poured onto ice (ca. 20 mL). After POCl ₃ was gone, the resulting precipitate was isolated by filtration and washed with H ₂ O (2 × 20 mL). The solid was dissolved in DCM (25 mL) and the solution was dried over MgSO ₄ and filtered. The solvent was removed under reduced pressure and the crude product was chromatographed on a 40 g pre-packed SiO ₂ column eluting with 0: 1 to 2: 3 EtOAc / hexane to give 3-tert-butyl-5- This yielded [4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridin-2-yl] -1-methyl-1H-pyrazole-4-carbonitrile. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.85 (d, J = 7.8 Hz, 1H), 7.68-7.76 (m, 2H), 7.62-7.68 (m , 1H), 7.60 (d, J = 7.6 Hz, 1H), 4.19 (s, 3H), 1.48 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₂ H ₁₈ ClF ₃ N ₆ : 459.1 (M + H); found: 459.2.

Step D: 3-tert-butyl-5- [4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridin-2-yl] -1-methyl-1H -Pyrazole-4-carbonitrile hydrochloride 3-tert-butyl-5- [4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridin-2-yl] A solution of -1-methyl-1H-pyrazole-4-carbonitrile (111 mg, 0.241 mmol, prepared as in the previous step) in EtOAc (1 mL) was added 1M HCl in Et ₂ O (0.241 mL, 0. 241 mmol). The resulting mixture was mixed well and the solvent was removed under reduced pressure to give 3-tert-butyl-5- [4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4 Yielded 5-c] pyridin-2-yl] -1-methyl-1H-pyrazole-4-carbonitrile hydrochloride. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.90 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.80 (t, J = 7.3 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 4.11 (s, 3H), 1.44 (s, 9H) . Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₂ H ₁₈ ClF ₃ N ₆ : 459.1 (M + H); found: 459.2.

  Following the procedures described in Example 16 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 17)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5- c] Pyridine hydrochloride (Compound # 71)

Step A: 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4 , 5-c] pyridine 2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4 A solution of 5-c] pyridine (101 mg, 0.232 mmol, the free base of compound # 74 prepared according to steps A, B and C of Example 16) in DCM (2 mL) was added SO ₂ Cl ₂ (28.3 μL, 0 .348 mmol) and the resulting mixture was stirred at room temperature for 14 hours. The resulting mixture was then diluted with MeOH (3 mL) and the solvent was removed under reduced pressure. The residue was chromatographed on a 25 g pre-packed SiO ₂ column eluting with 0: 1 to 3: 7 EtOAc / hexane to give 2- (5-tert-butyl-4-chloro-2-methyl- This gave 2H-pyrazol-3-yl) -4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.84 (d, J = 7.8 Hz, 1H), 7.69-7.76 (m, 1H), 7.68 (s, 1H), 7.62-7.67 (m, 1H), 7.59 (d, J = 7.6 Hz, 1H), 4.14 (s, 3H), 1.45 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₁ H ₁₈ Cl ₂ F ₃ N ₅ : 468.1 (M + H); found: 468.1.

Step B: 2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4 , 5-c] pyridine hydrochloride According to the procedure described in Step D of Example 16, 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-chloro- 6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine (62.7 mg, 0.134 mmol) and 1M HCl in Et ₂ O (0.134 mL, 0.134 mmol) To 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4 5- c] Pyridine hydrochloride was prepared. ¹ H-NMR (400 MHz, d ₆ -DMSO) δ: 7.90 (d, J = 7.8 Hz, 1H), 7.77-7.83 (m, 1H), 7.76 (s, 1H) 7.68-7.74 (m, 1H), 7.65 (d, J = 7.6 Hz, 1H), 4.07 (s, 3H), 1.41 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calculated for C ₂₁ H ₁₈ Cl ₂ F ₃ N ₅ : 468.1 (M + H); found: 468.1.

  Following the procedures described in Example 17 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 18)
3-tert-butyl-5- [7-methoxy-5- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b] pyridin-2-yl] -isoxazole-4-carbonitrile methane Sulfonate (Compound # 70)

4-Chloro-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine (prepared as described in Example 1) was reacted according to the process described in Step A of Example 9. The resulting compound was then prepared according to the process described in Example 25, Step C and Example 26, using 3-tert-butyl-4-cyano-isoxazole-5-carboxylic acid (prepared as described in Example J). To give the title compound. ¹ H-NMR (400 MHz, d ₆ -DMSO) δ: 7.89 (d, J = 7.8 Hz, 1H), 7.80 (t, J = 7.3 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.07 (s, 1H), 4.15 (s, 3H), 2.35 (s, 3H) , 1.47 (s, 9H). Mass spectrum (. LCMS, ESI pos): C 22 H 18 F 3 N 5 O 2 Calculated: 442.2 (M + H); Found: 442.2.

  Following the procedures described in Example 18 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 19)
2- (3-tert-Butyl-isoxazol-5-yl) -4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine hydrochloride (Compound # 73) )

Step A: 3-tert-butyl-isoxazole-5-carboxylic acid [4-amino-2-chloro-6- (2-trifluoromethyl-phenyl) -pyridin-3-yl] -amide and 3-tert- Butyl-isoxazole-5-carboxylic acid [3-amino-2-chloro-6- (2-trifluoromethyl-phenyl) -pyridin-4-yl] -amide 3-tert-butyl-4-isoxazole-5 Carboxylic acid (72.8 mg, 0.430 mmol, prepared as in Example I above) was dissolved in DCM (2 mL) and DMF (10 μL) and oxalyl chloride (51.2 μL, 0.587 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The resulting residue was dissolved in DCM (2 mL).

2-Chloro-6- (2-trifluoromethyl-phenyl) -pyridine-3,4-diamine (113 mg, 0.391 mmol, prepared as in Example 16, Step B) was dissolved in DCM (3 mL), Then DIEA (136 μL, 0.782 mmol) was added. The acid chloride solution prepared above was added dropwise to the stirred mixture, which was then stirred at room temperature for an additional 18 hours. The solvent was removed under reduced pressure and the resulting residue was chromatographed on a pre-packed 24 g SiO ₂ column eluting with 0: 1 to 3: 2 EtOAc / hexane to give 3-tert-butyl. -Isoxazole-5-carboxylic acid [4-amino-2-chloro-6- (2-trifluoromethyl-phenyl) -pyridin-3-yl] -amide and 3-tert-butyl-isoxazole-5-carvone The acid [3-amino-2-chloro-6- (2-trifluoromethyl-phenyl) -pyridin-4-yl] -amide was obtained. Mass spectrum (. LCMS, ESI pos): C 20 H 18 ClF 3 N 4 O 2 Calculated: 439.1 (M + H); Found: 439.1.

Step B: 2- (3-tert-butyl-isoxazol-5-yl) -4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine 3-tert -Butyl-isoxazole-5-carboxylic acid [4-amino-2-chloro-6- (2-trifluoromethyl-phenyl) -pyridin-3-yl] -amide (73.9 mg, 0.168 mmol, previous Prepared as in step) was dissolved in AcOH (1 mL) and the resulting solution was heated to 100 ° C. for 14 h. The resulting mixture was cooled to room temperature and poured into H ₂ O (20 mL). The aqueous phase was extracted with DCM (3 × 10 mL) and the combined extracts were washed with a saturated NaHCO ₃ solution (20 mL). The organic layer was dried over MgSO ₄ , filtered and the solvent removed under reduced pressure. The residue was dissolved in POCl ₃ (1 mL) and heated at 100 ° C. for 16 hours. The resulting mixture was cooled to room temperature and poured onto ice (ca. 20 mL). After the POCl ₃ was gone, the precipitate was isolated by filtration and washed with H ₂ O (2 × 20 mL). The solid was dissolved in DCM (25 mL) and the solution was dried over MgSO ₄ and filtered. The solvent was removed under reduced pressure and the crude product was chromatographed on a 24 g pre-packed SiO ₂ column eluting with 0: 1 to 2: 3 EtOAc / hexane to give 2- (3-tert-butyl). -Isoxazol-5-yl) -4-chloro-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine was produced. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.84 (d, J = 7.8 Hz, 1H), 7.69-7.77 (m, 1H), 7.62-7.68 (m , 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.30 (s, 1H), 1.43 (s, 9H). Mass spectrum (. LCMS, ESI pos): C 20 H 16 ClF 3 N 4 O Calculated: 421.1 (M + H); Found: 421.1.

(Example 20)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -5- (2-chloro-phenyl) -1H-imidazo [4,5-b] pyridine (compound # 23)

Step A: 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl) -amide 6-bromo-3-nitro- A solution of pyridin-2-ylamine (750 mg, 3.44 mmol) in THF (20 mL) was treated with NaH (413 mg, 10.3 mmol) at room temperature for 1 hour. At the same time, a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (969 mg, 4.47 mmol, prepared as described in Example B) in DCM (20 mL) was added at room temperature. Treated with oxalyl chloride (390 μL, 4.47 mmol) and DMF (4 drops) for 1 hour. The acid chloride solution was concentrated to dryness under reduced pressure, taken up in THF (10 mL) and added to the sodium anilide solution. The resulting mixture was stirred at room temperature for 15 minutes, quenched with saturated aqueous NH ₄ Cl (50 mL) and extracted twice with EtOAc (60 mL, 20 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 40 g SEPRA Si 50 SPE column (Isco system: flow rate = 25 mL / min; eluent = EtOAc / hexane, 1:99 v / v over 1 min, then 1:99 to 3 over 40 min. To 17 v / v), 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl) as a pale yellow solid -Gave an amide. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 10.48 (br.s., 1H), 8.31 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 8.6 Hz) , 1H), 4.12 (s, 3H), 1.42 (s, 9H). Mass spectrum (LCMS, APCI pos.): Calculated for C ₁₄ H ₁₅ BrClN ₅ O ₃ : 416.0 (M + H); found: 416.1.

Step B: 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6- (2-chloro-phenyl) -3-nitro-pyridin-2-yl] -amide 5- tert-Butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl) -amide (200 mg, 0.480 mmol, as described in the previous step) Prepared in DME (20 mL) / water (5 mL) was treated with 2-chlorophenylboronic acid (78.8 mg, 0.504 mmol) and cesium carbonate (469 mg, 1.44 mmol). The resulting mixture was degassed via sonication, placed under Ar, treated with PdCl ₂ (dppf) · DCM (19.6 mg, 0.0240 mmol) and heated to 90 ° C. for 3 hours. The cooled mixture was then diluted with water (40 mL) and extracted twice with EtOAc (50 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 24 g SEPRA Si 50 SPE column (Isco system: flow rate = 20 mL / min; eluent = EtOAc / hexane, 1:99 v / v over 10 minutes, then 1: 99-3 over 40 minutes. To 17 v / v), as a yellow solid, 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6- (2-chloro-phenyl) -3-nitro-pyridine Yielded -2-yl] -amide. Mass spectrum (. LCMS, APCI pos): Calculated for _{C 20 H 19 Cl 2 N 5} O 3: 448.1 (M + H); Found: 448.0.

Step C: 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -5- (2-chloro-phenyl) -1H-imidazo [4,5-b] pyridine 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6- (2-chloro-phenyl) -3-nitro-pyridin-2-yl] -amide (157 mg,. A solution of 350 mmol, prepared as described in the previous step) in acetic acid (5 mL) was treated with iron powder (97.8 mg, 1.75 mmol) and heated to 100 ° C. for 3 hours. The cooled mixture was then concentrated under reduced pressure, taken up in water (50 mL) and extracted twice with EtOAc (50 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 12 g SEPRA Si 50 SPE column (Isco system: flow rate = 15 mL / min; eluent = EtOAc / hexane, 1:99 v / v over 10 minutes, then 1:99 to 3 over 40 minutes. To 17 v / v), 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -5- (2-chloro-phenyl) -1H- was obtained as a white solid. This gave imidazo [4,5-b] pyridine. Mass spectrum (. LCMS, APCI pos): Calculated for _{C 20 H 19 Cl 2 N 5} : 400.1 (M + H); Found: 400.2.

  Following the procedures described in Example 20 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 21)
8- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -6-methyl-2- (2-trifluoromethyl-phenyl) -7H-printed trifluoroacetate (Compound # 35)

Step A: 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [6-methyl-5-nitro-2- (2-trifluoromethyl-phenyl) -pyrimidin-4-yl] -amide 6-Methyl-5-nitro-2- (2-trifluoromethyl-phenyl) -pyrimidin-4-ylamine (150 mg, 0.503 mmol, prepared as described in Example 2, Step A) in THF (10 mL) The solution was treated with NaH (60.4 mg, 1.51 mmol, 60% dispersion in oil) and the resulting mixture was allowed to stir for 30 minutes. 5-tert-Butyl-2-methyl-2H-pyrazole-3-carbonyl chloride (131 mg, 0.654 mmol) was added as a THF (3 mL) solution. After 15 minutes, the mixture was quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted twice with EtOAc (25 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 12 g SEPRA Si 50 SPE column (Isco system: flow rate = 15 mL / min; eluent = EtOAc / hexane, 1:99 v / v over 10 minutes, then 1:99 to 1 over 40 minutes. : 4v / v) to give 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [6-methyl-5-nitro-2- (2-trifluoromethyl-) as a colorless glassy solid. Phenyl) -pyrimidin-4-yl] -amide. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 9.10 (s, 1H), 7.79-7.86 (m, 2H), 7.60-7.72 (m, 2H), 6.64 (S, 1H), 4.14 (s, 3H), 2.83 (s, 3H), 1.33 (s, 9H). Mass spectrum (LCMS, APCI pos.): Calculated for C ₂₁ H ₂₁ F ₃ N ₆ O ₃ : 463.2 (M + H); found: 463.2.

Step B: 5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid [5-amino-6-methyl-2- (2-trifluoromethyl-phenyl) -pyrimidin-4-yl] -amide 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [6-methyl-5-nitro-2- (2-trifluoromethyl-phenyl) -pyrimidin-4-yl] -amide (226 mg, A solution of 0.490 mmol, prepared as described in the previous step) in ethanol (10 mL) / water (5 mL) with ammonium chloride (262 mg, 4.90 mmol) and iron powder (137 mg, 2.45 mmol), and the mixture Was heated to 50 ° C. for 4 hours. Ethanol was removed under reduced pressure and the resulting residue was diluted with water (20 mL) and extracted twice with EtOAc (30 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 12 g SEPRA Si 50 SPE column (Isco system: flow rate = 20 mL / min; eluent = EtOAc / hexane, 1:99 v / v over 10 minutes, then 1:99 to 1 over 40 minutes. : 4v / v) to give 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [5-amino-6-methyl-2- (2-trifluoromethyl-phenyl) as an off-white solid Yielded -pyrimidin-4-yl] -amide. Mass spectrum (LCMS, APCI pos.): Calculated for C ₂₁ H ₂₃ F ₃ N ₆ O: 433.2 (M + H); found: 433.2.

Step C: 8- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -6-methyl-2- (2-trifluoromethyl-phenyl) -7H-printed trifluoroacetate salt 5- tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid [5-amino-6-methyl-2- (2-trifluoromethyl-phenyl) -pyrimidin-4-yl] -amide (45.8 mg, A solution of 0.106 mmol, prepared as described in the previous step) in 1,4-dioxane (10 mL) was treated with CSA (49.2 mg, 0.213 mmol) and 100 ° C. for 3 h under reflux condenser. Heated. The cooled mixture was then diluted with water (20 mL) and extracted twice with EtOAc (25 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a C18 column by RP-HPLC eluting with a linear gradient of 10-80% CH ₃ CN 0.1% TFA / H ₂ O over 25 min to give 8- (5 -Tert-Butyl-2-methyl-2H-pyrazol-3-yl) -6-methyl-2- (2-trifluoromethyl-phenyl) -7H-printed trifluoroacetate was obtained. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.77 (d, J = 7.6 Hz, 1H), 7.57 to 7.70 (m, 3H), 6.87 (s, 1H), 4.27 (s, 3H), 2.80 (s, 3H), 1.28 (s, 9H). Mass spectrum (LCMS, APCI pos.): Calculated for C ₂₁ H ₂₁ F ₃ N ₆ : 415.2 (M + H); found: 415.2.

(Example 22)
2- (3-tert-Butyl-isoxazol-5-yl) -5- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b] pyridine (Compound # 31)

Step A: 3-tert-butyl-isoxazole-5-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl) -amide 6-bromo-3-nitro-pyridin-2-ylamine (500 mg, 2 .29 mmol) in THF (10 mL) was treated with NaH (275 mg, 6.88 mmol) at room temperature for 1 h. At the same time, a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (524 mg, 3.10 mmol, prepared as described in Example I) in DCM (10 mL) was added oxalyl chloride (270 μL, 3 mL) at room temperature for 1 hour. .10 mmol) and DMF (2 drops). The acid chloride solution was concentrated to dryness under reduced pressure, taken up in THF (10 mL) and added to the sodium anilide solution. The resulting mixture was stirred at room temperature for 15 minutes, quenched with saturated aqueous NH ₄ Cl (50 mL) and extracted twice with EtOAc (50 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 40-g SEPRA Si 50 SPE column (Isco system: flow rate = 25 mL / min; eluent = EtOAc / hexane, 1:99 v / v over 1 min, then 1:99 over 40 min. To 3:17 v / v) yielded 3-tert-butyl-isoxazole-5-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl) -amide as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 10.85 (br.s., 1H), 8.37 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 8.6 Hz) , 1H), 7.03 (s, 1H), 1.39 (s, 9H). Mass spectrum (LCMS, APCI pos.): Calculated for C ₁₃ H ₁₃ BrN ₄ O ₄ : 369.0 (M + H); found: 369.0.

Step B: 6- (2-Trifluoromethyl-phenyl) -3-nitro-pyridin-2-ylamine 3-tert-butyl-isoxazole-5-carboxylic acid (6-bromo-3-nitro-pyridin-2- Yl) -amide (139 mg, 0.377 mmol, prepared as described in previous step) in DME (15 mL) / water (5 mL) solution of 2-trifluoromethylphenylboronic acid (85.8 mg, 0.452 mmol) And treated with cesium carbonate (245 mg, 0.753 mmol). The resulting mixture was degassed via sonication, placed under Ar, treated with PdCl ₂ (dppf) · DCM (15.4 mg, 0.019 mmol) and heated to 80 ° C. for 18 hours. The cooled mixture was diluted with water (50 mL) and extracted twice with EtOAc (50 mL, 25 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: flow rate = 15 mL / min; eluent = EtOAc / hexane, 1:99 v / v over 10 minutes, then 1:99 over 40 minutes. To 3:17 v / v) to give 6- (2-trifluoromethyl-phenyl) -3-nitro-pyridin-2-ylamine as a yellow solid. Mass spectrum (LCMS, APCI pos.): Calculated for C ₁₂ H ₈ F ₃ N ₃ O ₂ : 284.1 (M + H); found: 284.0.

Step C: 3-tert-butyl-isoxazole-5-carboxylic acid [3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amide 6- (2-trifluoromethyl- Phenyl) -3-nitro-pyridin-2-ylamine (69.0 mg, 0.244 mmol, prepared as described in the previous step) in THF (10 mL) was added NaH (29.2 mg, 0.731 mmol, 60% dispersion in oil). At the same time, a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (49.5 mg, 0.292 mmol, prepared as described in Example L) in DCM (10 mL) was added oxalyl chloride (25 mL) at room temperature for 1 hour. .5 μL, 0.292 mmol) and DMF (2 drops). The resulting mixture was concentrated under reduced pressure, taken up in THF (10 mL) and added to the sodium anilide solution. The resulting mixture was then allowed to stir at room temperature for 15 minutes, quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted twice with EtOAc (20 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 4-g SEPRA Si 50 SPE column (Isco system: flow rate = 10 mL / min; eluent = EtOAc / hexane, 1:99 v / v over 5 minutes, then 1:99 over 40 minutes. To 9: 9 v / v) to give 3-tert-butyl-isoxazole-5-carboxylic acid [3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] as a white solid -Gave an amide. Mass spectrum (. LCMS, APCI pos): Calculated for _{C 20 H 17 F 3 N 4} O 4: 435.1 (M + H); Found: 435.1.

Step D: 2- (3-tert-butyl-isoxazol-5-yl) -5- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b] pyridine 3-tert-butyl-iso Oxazole-5-carboxylic acid [3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amide (78.0 mg, 0.180 mmol, prepared as described in the previous step) Was treated with iron powder (50.1 mg, 0.898 mmol) and heated to 100 ° C. for 2 hours. The volume of acetic acid was reduced to 2 mL by concentrating under reduced pressure and saturated aqueous NaHCO ₃ (50 mL) was added. The resulting mixture was extracted twice with EtOAc (60 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 4-g SEPRA Si 50 SPE column (Isco system: flow rate = 10 mL / min; eluent = EtOAc / hexane, 1:99 v / v over 5 minutes, then 1:99 over 40 minutes. To 9: 9 v / v) and 2- (3-tert-butyl-isoxazol-5-yl) -5- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5 as a white solid. -B] gave pyridine. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 10.06 (br.s., 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 8.1 Hz) , 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.52 to 7.60 (m, 2H), 7.46 (d, J = 8.3 Hz, 1H), 7.07 (S, 1H), 1.42 (s, 9H). Mass spectrum (. LCMS, APCI pos): C 20 H 17 F 3 N 4 O Calculated: 387.1 (M + H); Found: 387.1.

  Following the procedures described in Example 22 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 23)
2- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -5- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b] pyridine (Compound # 34)

Step A: 5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid (5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-[3-nitro-6- (2 -Trifluoromethyl-phenyl) -pyridin-2-yl] -amide 3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine (200 mg, 0.706 mmol, step of Example 22 above) A solution of (prepared as described in B) in THF (15 mL) was treated with NaH (84.7 mg, 2.12 mmol) at room temperature for 1 h. The resulting mixture is treated with a solution of 5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl chloride (156 mg, 0.777 mmol) in THF (6 mL) and stirred at room temperature for 15 minutes. I kept it. The mixture was quenched with saturated aqueous NH ₄ Cl (25 mL) and extracted twice with EtOAc (35 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: flow rate = 20 mL / min; eluent = EtOAc / hexane, 1:99 v / v over 5 minutes, then 1:99 over 40 minutes. To 1: 9 v / v) to give 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid (5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl as a yellow solid) )-[3-Nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-yl] -amide. Mass spectrum (. LCMS, APCI pos): Calculated for _{C 30 H 32 F 3 N 7} O 4: 612.3 (M + H); Found: 612.1.

Step B: 2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -5- (2-trifluoromethyl-phenyl) -1H-imidazo [4,5-b] pyridine 5- tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid (5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-[3-nitro-6- (2-trifluoromethyl- A solution of (phenyl) -pyridin-2-yl] -amide (339 mg, 0.554 mmol, prepared as described in the previous step) is taken up in an acetic acid (10 mL) and treated with iron powder (124 mg, 2.22 mmol). And heated to 90 ° C. for 15 hours. The resulting mixture was concentrated to a volume of ₃ mL, treated with saturated aqueous NaHCO ₃ (75 mL) and extracted twice with EtOAc (75 mL, 40 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: flow rate = 20 mL / min; eluent = EtOAc / hexane, 1:19 v / v over 5 minutes, then 1:19 over 40 minutes. To 1: 4 v / v) to give 2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -5- (2-trifluoromethyl-phenyl) -1H- as a white solid. This gave imidazo [4,5-b] pyridine. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.13 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.61 to 7.68 ( m, 1H), 7.52 to 7.59 (m, 2H), 7.40 (d, J = 8.1 Hz, 1H), 6.56 (s, 1H), 4.37 (s, 3H) , 1.37 (s, 9H). Mass spectrum (LCMS, APCI pos.): Calculated for C ₂₁ H ₂₀ F ₃ N ₅ : 400.2 (M + H); found: 400.2.

  Following the procedures described in Example 23 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 24)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4- (4-methyl-piperazin-1-yl) -6- (2-trifluoromethyl-phenyl) ) -3H-imidazo [4,5-c] pyridine methanesulfonate (compound # 28)

Step A: 6-chloro-2- (4-methyl-piperazin-1-yl) -3-nitro-pyridin-4-ylamine 2,6-dichloro-3-nitro-pyridin-4-ylamine (0.500 g, 2.40 mmol) in DMF (5 mL) was treated with K ₂ CO ₃ (1.66 g, 12.0 mmol) and 1-methylpiperazine (0.267 mL, 2.40 mmol) at room temperature for 18 hours. The resulting mixture was diluted with water (75 mL) and extracted 3 times with EtOAc (50 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: flow rate = 15 mL / min; eluent = EtOAc-hexane, 3: 1 v / v over 5 minutes, then 3: 1 over 40 minutes. To 1: 0 v / v) yielded 6-chloro-2- (4-methyl-piperazin-1-yl) -3-nitro-pyridin-4-ylamine as a light yellow solid. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 6.22 (s, 1H), 3.39 to 3.45 (m, 4H), 2.49 to 2.55 (m, 4H), 2. 34 (s, 3H). Mass spectrum (LCMS, APCI pos.): Calcd for C ₁₀ H ₁₄ ClN ₅ O ₂ : 272.1 (M + H); found: 272.1.

Step B: 2- (4-Methyl-piperazin-1-yl) -3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-ylamine 6-chloro-2- (4-methyl-piperazine A solution of -1-yl) -3-nitro-pyridin-4-ylamine (578 mg, 2.13 mmol, prepared as described in the previous step) in 1,4-dioxane (20 mL) was added to K ₃ PO ₄ (2. 03 g, 9.58 mmol), 1,1′-bis (di-tert-butylphosphino) ferrocene (101 mg, 0.213 mmol) and 2-trifluoromethylphenylboronic acid (910 mg, 4.79 mmol). The resulting mixture was degassed via sonication, Pd (OAc) ₂ (47.8 mg, 0.213 mmol) was added and the mixture was heated to 80 ° C. for 18 hours. The cooled mixture was diluted with water (50 mL) and extracted twice with EtOAc (60 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 40-g SEPRA Si 50 SPE column (Isco system: flow rate = 20 mL / min; eluent = EtOAc-hexane, 3: 1 v / v over 5 minutes, then 3: 1 over 40 minutes. To 1: 0 v / v) to give 2- (4-methyl-piperazin-1-yl) -3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-ylamine as an orange yellow solid Produced. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.74 (d, J = 7.6 Hz, 1H), 7.55 to 7.61 (m, 1H), 7.45 to 7.54 (m, 2H), 6.13 (s, 1H), 6.02 (br.s., 2H), 3.46-3.52 (m, 4H), 2.44-2.50 (m, 4H), 2.32 (s, 3H). Mass spectrum (LCMS, APCI pos.): Calculated for C ₁₇ H ₁₈ F ₃ N ₅ O ₂ : 382.1 (M + H); found: 382.1.

Step C: 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2- (4-methyl-piperazin-1-yl) -3-nitro-6- (2-tri Fluoromethyl-phenyl) -pyridin-4-yl] -amide 2- (4-methyl-piperazin-1-yl) -3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-ylamine ( A solution of 240 mg, 0.630 mmol, prepared as described in the previous step) in THF (10 mL) was treated with NaH (75.6 mg, 1.89 mmol, 60% dispersion in mineral oil) at room temperature for 1 hour. At the same time, a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (164 mg, 0.756 mmol, prepared as described in Example B) in DCM (10 mL) was brought to room temperature. For one hour with oxalyl chloride (66.0 μL, 0.756 mmol) and DMF (2 drops). The resulting mixture was concentrated under reduced pressure, taken up in THF (6 mL) and added to the sodium anilide solution at room temperature. The resulting mixture was stirred at room temperature for 30 minutes, quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted three times with EtOAc (25 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: flow rate = 15 mL / min; eluent = EtOAc / hexane, 3: 2 v / v over 5 min, then 3: 2 over 40 min. To 4: 1 v / v) to give 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2- (4-methyl-piperazin-1-yl) as an orange yellow solid ) -3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-yl] -amide. Mass spectrum (. LCMS, APCI pos): measurement of _{C 26 H 29 ClF 3 N 7} O 3: 580.2 (M + H); Found: 580.2.

Step D: 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4- (4-methyl-piperazin-1-yl) -6- (2-trifluoro Methyl-phenyl) -3H-imidazo [4,5-c] pyridine 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2- (4-methyl-piperazine-1- Yl) -3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-yl] -amide (300 mg, 0.517 mmol, prepared as described in previous step) in AcOH (10 mL) Was treated with iron powder (86.7 mg, 1.55 mmol) and heated to 100 ° C. for 5 hours. The mixture was concentrated under reduced pressure, treated with saturated aqueous NaHCO ₃ (25 mL) and extracted three times with EtOAc (30 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: flow rate = 10 mL / min; eluent = EtOAc-hexane, 1:99 v / v over 5 minutes, then 1:99 over 40 minutes. To 3:17 v / v) to give 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4- (4-methyl-piperazine- 1-yl) -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine was produced. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 9.99 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.56 to 7.61 (m, 2H), 7 .45 to 7.52 (m, 1H), 6.95 (s, 1H), 4.30 (s, 7H), 2.59 (t, J = 4.9 Hz, 4H), 2.36 (s) , 3H), 1.45 (s, 9H). Mass spectrum (. LCMS, APCI pos): Calculated for _{C 26 H 29 ClF 3 N 7} : 532.2 (M + H); Found: 532.2.

Step E: 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4- (4-methyl-piperazin-1-yl) -6- (2-trifluoro Methyl-phenyl) -3H-imidazo [4,5-c] pyridine methanesulfonate 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4- (4 -Methyl-piperazin-1-yl) -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine (158 mg, 0.297 mmol, prepared as described in the previous step) Of DCM in 10 mL was treated with methanesulfonic acid (19.2 μL, 0.297 mmol) at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure, triturated with hexane and filtered. The solid was air dried and placed under high vacuum for 30 minutes to give 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4- ( 4-methyl-piperazin-1-yl) -6- (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine methanesulfonate was obtained. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.83 (d, J = 8.3 Hz, 1H), 7.68-7.74 (m, 1H), 7.58-7.65 (m , 2H), 7.20 (s, 1H), 5.52 (d, J = 13.1 Hz, 2H), 4.12 (s, 3H), 3.64 (d, J = 11.6 Hz, 2H) ), 3.45 to 3.58 (m, 2H), 3.26 (br.s., 2H), 2.96 (s, 3H), 2.69 (s, 4H), 1.45 (s) , 9H). Mass spectrum (. LCMS, APCI pos): Calculated for _{C 26 H 29 ClF 3 N 7} : 532.2 (M + H); Found: 532.2.

  Following the procedures described in Example 24 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 25)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] Pyridine (compound # 11)

Step A: 6-Chloro-2-methoxy-3-nitro-pyridin-4-ylamine 2,6-Dichloro-3-nitro-pyridin-4-ylamine (20.0 g, 96.1 mmol) stirred in MeOH (100 mL) To the solution was added 0.5 M NaOMe in MeOH (423 mL, 211 mmol) dropwise. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was then concentrated to about ３ volume and slowly poured into saturated NH ₄ Cl solution (200 mL). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined EtOAc extracts were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to yield a light brown solid that was suspended in hexane (500 mL) and sonicated for 10 minutes. The resulting solid was collected by suction filtration and dried with suction to yield 6-chloro-2-methoxy-3-nitro-pyridin-4-ylamine as a powder. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.39 (s, 1H), 6.28 (br s, 2H), 4.05 (s, 3H).

Step B: 6- (2-Chloro-phenyl) -2-methoxy-3-nitro-pyridin-4-ylamine 6-Chloro-2-methoxy-3-nitro-pyridin-4-ylamine (8.90 g, 43. A solution of 7 mmol, prepared as described in the previous step) in 1,4-dioxane (200 mL) / water (100 mL) under Ar was treated with Cs ₂ CO ₃ (35.6 g, 109 mmol) and 2-chlorophenylboronic acid (10 .2 g, 65.5 mmol). To the resulting mixture was added Cl ₂ Pd (dppf) · DCM (3.50 g, 4.30 mmol) and the mixture was then heated to 90 ° C. for 15 hours. The cooled mixture was diluted with EtOAc (500 mL) and washed with water (500 mL). The aqueous layer was further extracted twice with EtOAc (3 × 300 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified on silica (0: 100-50: 50 EtOAc / hexanes) to yield a pale yellow solid. This solid was dissolved in EtOAc (200 mL) with heating and hexane (150 mL) was added. The resulting solution was concentrated until the solution became turbid and heated to yield a clear solution that was allowed to stand overnight at room temperature. The purified crystal was collected by suction filtration. This recrystallization procedure was repeated twice to yield 6- (2-chloro-phenyl) -2-methoxy-3-nitro-pyridin-4-ylamine. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.59-7.66 (m, 1H), 7.43-7.51 (m, 1H), 7.31-7.39 (m, 2H) , 6.69 (s, 1H), 6.11 (br.s., 2H), 4.07 (s, 3H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₁₂ H ₁₀ N ₃ O ₃ Cl: 280.0 (M + H), found: 280.1.

Step C: 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5 -C] pyridine 6- (2-chloro-phenyl) -2-methoxy-3-nitro-pyridin-4-ylamine (8.10 g, 29.0 mmol, prepared as described in previous step) in THF (200 mL) ) The solution was treated with NaH (3.47 g, 86.8 mmol, 60% dispersion in oil) at 0 ° C. for 1 hour. At the same time, a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (6.90 g, 31.8 mmol, prepared as described in Example B) in DCM (200 mL) was added. Treated with oxalyl chloride (3.2 mL, 36 mmol) and DMF (50 μL) at 0 ° C. and stirred at room temperature for 1 hour. The volatile components were removed under reduced pressure and the resulting residue was dried under reduced pressure for 15 minutes, taken up in THF (20 mL) and added to the sodium anilide solution at 0 ° C. The resulting mixture was stirred at room temperature for 30 minutes, quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted with EtOAc (3 × 100 mL). The combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The resulting solid was suspended in hexane (200 mL), sonicated for 10 minutes and filtered with suction to give 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3- as a light brown solid. This gave the carboxylic acid [6- (2-chloro-phenyl) -2-methoxy-3-nitro-pyridin-4-yl] -amide.

5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6- (2-chloro-phenyl) -2-methoxy-3-nitro-pyridin-4-yl] -amide ( A solution of 9.10 g, 32.6 mmol, prepared as described in the previous step) in AcOH (50 mL) was treated with iron powder (6.80 g, 122 mmol) and heated to 100 ° C. for 3 hours. The resulting mixture was cooled to room temperature and treated with EtOAc (100 mL). The resulting mixture was then filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified on silica (0: 100-100: 0 EtOAc / hexanes) to yield a white solid. The resulting solid was dissolved in Et ₂ O (200 mL) with heating and sonication. Hexane (50 mL) was added and the resulting mixture was concentrated to the beginning of precipitation. The solution was allowed to stand overnight at room temperature, and the resulting solid was collected by suction filtration to give 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- ( This gave 2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] pyridine. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.76-7.58 (m, 1H), 7.49 (m, 2H), 7.39 (m, 2H), 4.16 (s, 3H), 4.04 (s, 3H), 1.44 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₂₁ H ₂₁ N ₅ OCl ₂ : 430.1 (M + H), found: 430.2.

(Example 26)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] Pyridine methanesulfonate (Compound # 11)

2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] A solution of pyridine (159 mg, 0.370 mmol, prepared as described in Example 25) in DCM (10 mL) was treated with methanesulfonic acid (35.6 mg, 0.370 mmol) at room temperature for 1 hour. The solution was concentrated under reduced pressure and the resulting solid was triturated with hexane, filtered, washed with hexane, air dried and placed under high vacuum for 30 minutes to give 2- (5- tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] pyridinemethanesulfonate Produced. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.64 to 7.69 (m, 2H), 7.62 to 7.64 (m, 1H), 7.50 to 7.61 (m, 2H) ), 4.75 to 4.81 (m, 3H), 4.16 (s, 3H), 2.70 (s, 3H), 1.46 (s, 9H). Mass spectrum (LCMs, APCI pos.) Calculated for C ₂₁ H ₂₁ N ₅ OCl ₂ : 430.1 (M + H), found: 430.2.

(Example 27)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] Pyridine trifluoroacetate (Compound # 11)

5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6- (2-chloro-phenyl) -2-methoxy-3-nitro-pyridin-4-yl] -amide ( To a HOAc (10 mL) solution of 96.3 mg, 0.201 mmol, prepared as described in Example 25, Step C), iron powder (56.2 mg, 1.01 mmol) was added and the resulting mixture was Heated to 100 ° C. for 5 hours. This HOAc was then removed under reduced pressure. The resulting mixture was partitioned between EtOAc (30 mL) and saturated aqueous NaHCO ₃ (20 mL). This organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: flow rate = 20 mL / min; eluent = EtOAc / hexane, 1:99 v / v over 10 minutes, then over 40 minutes 1:99 to 1: 4 v / v). The resulting residue was further purified on a C18 column by RP-HPLC eluting with a linear gradient of 40-100% CH ₃ CN 0.1% TFA / H ₂ O over 20 minutes as a white solid. 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] This gave pyridine trifluoroacetate. ¹ H-NMR (CD ₃ OD) δ: 7.69 (dd, J = 7.2, 2.1 Hz, 1H), 7.50-7.56 (m, 2H), 7.37-7.46 (M, 2H), 4.25 (s, 3H), 4.05 (s, 3H), 1.45 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₂₁ H ₂₁ N ₅ OCl ₂ : 430.1 (M + H), found: 430.2.

(Example 28)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] Pyridine potassium salt (Compound # 11)

2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] KOMe (1.90 g, 25.7 mmol) in MeOH (20 mL) at 0 ° C. in a solution of pyridine (11.0 g, 25.7 mmol, prepared as described in Example 25) in THF (20 mL) / MeOH (20 mL). ) The solution was added dropwise. The resulting mixture was stirred at room temperature for 1 hour and concentrated. The resulting thick syrup was dried overnight at 80 ° C. under reduced pressure to give 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl as a white foam. ) -6- (2-Chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] pyridine potassium salt. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.66-7.69 (m, 1H), 7.46-7.50 (m, 1H), 7.43 (s, 1H), 7. 28-7.39 (m, 2H), 4.12 (s, 3H), 3.90 (s, 3H), 1.44 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₂₁ H ₂₁ N ₅ OCl ₂ : 430.1 (M + H), found: 430.2.

(Example 29)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] Pyridine hydrochloride (Compound # 11)

According to the procedure described in Step C of Example 2, replacing 6M HCl in IPA with 2M HCl in Et ₂ O, 2- (5-tert-butyl-4-chloro-2-methyl-2H— Pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] pyridine (prepared as described in Example 25) to 2- (5-tert -Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] pyridine hydrochloride was prepared . ¹ H-NMR (CD ₃ OD) δ: 7.69-7.65 (m, 1H), 7.53 to 7.60 (m, 2H), 7.42 to 7.49 (m, 2H), 4.40 (s, 3H), 4.10 (s, 3H), 1.47 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₂₁ H ₂₁ N ₅ OCl ₂ : 430.1 (M + H), found: 430.2.

(Example 30)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] Pyridine sodium salt (compound # 11)

Following the procedure described in Step E of Example 5, 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4- 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) from methoxy-3H-imidazo [4,5-c] pyridine (prepared as described in Example 25) -6- (2-Chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] pyridine sodium salt was prepared. ¹ H-NMR (CD ₃ OD) δ: 7.67 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.26-7.39 (m, 2H), 4.11 (s, 3H), 3.87 (s, 3H), 1.44 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₂₁ H ₂₁ N ₅ OCl ₂ : 430.1 (M + H), found: 430.2.

  Following the procedures described in Examples 25-30 above, the following representative compounds of the invention are prepared by substituting suitably selected and substituted reagents, starting materials and conditions that will be readily apparent to those skilled in the art. did.

(Example 31)
2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-morpholin-4-yl-6- (2-trifluoromethyl-phenyl) -3H-imidazo [ 4,5-c] pyridine (Compound # 59)

Step A: 6-Chloro-2-morpholin-4-yl-3-nitro-pyridin-4-ylamine 2,6-dichloro-3-nitro-pyridin-4-ylamine (970 mg, 4.66 mmol) in DMF (5 mL) ) To the solution was added K ₂ CO ₃ (3.20 g, 23.0 mmol) followed by morpholine (0.410 mL, 4.60 mmol). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water and extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was purified on silica (0: 100-50: 50 EtOAc-hexane) to give 6-chloro-2-morpholin-4-yl-3-nitro-pyridin-4-ylamine. . ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 5.99 to 6.20 (m, 3H), 3.72 to 3.82 (m, 4H), 3.40 to 3.50 (m, 4H) .

Step B: 2-morpholin-4-yl-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-ylamine According to the procedure described in Example 24, Step B Instead, reagents, starting materials and conditions, suitably selected and substituted as apparent, were used to replace 6-chloro-2-morpholin-4-yl-3-nitro-pyridin-4-ylamine (previous step 2-morpholin-4-yl-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-4-ylamine was prepared from ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.76 (d, J = 7.8 Hz, 1H), 7.56 to 7.64 (m, 1H), 7.45 to 7.56 (m, 2H), 6.18 (s, 1H), 6.05 (br.s., 2H), 3.73 to 3.81 (m, 4H), 3.44 to 3.52 (m, 4H).

Step C: 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-morpholin-4-yl-6- (2-trifluoromethyl-phenyl) -3H -Imidazo [4,5-c] pyridine 2 Reagents, starting materials and conditions were used instead, suitably selected and substituted according to Step C of Example 25, as would be readily apparent to one skilled in the art. -(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -4-morpholin-4-yl-6- (2-trifluoromethyl-phenyl) -3H-imidazo [4 , 5-c] pyridine was prepared. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.76 to 7.80 (m, 1H), 7.63 to 7.69 (m, 1H), 7.52 to 7.61 (m, 3H) ), 4.15 to 4.21 (m, 4H), 4.10 (s, 3H), 3.81 to 3.87 (m, 4H), 1.44 (s, 9H). Mass spectrum (. LCMs, ESI pos) C 25 H 26 ClF 3 N 5 O Calculated: 419.2 (M + H), Found: 419.4.

(Example 32)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6 (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] pyridine-4 Carbonitrile (compound # 60)

Step A: 4-Amino-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridine-2-carbonitrile 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (186 mg, 0.937 mmol) in 1,4-dioxane (5 mL) was added to K ₃ PO ₄ (1.00 g, 5.10 mmol), 2-trifluoromethylphenylboronic acid (178 mg, 0.937 mmol), 1,1′- Treated with bis (di-tert-butylphosphino) ferrocene (60.5 mg, 0.128 mmol) and Pd (OAc) ₂ (28.6 mg, 0.128 mmol). The resulting mixture was stirred at 80 ° C. overnight. The cooled mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). The aqueous layer was extracted twice with EtOAc (30 mL) and the combined extracts were dried over MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified on silica (0: 100-100: 0 EtOAc-hexanes) to give 4-amino-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridine-2- Carbonitrile was produced. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.79 (m, 1H), 7.67 (m, 4H), 7.52 (m, 1H), 7.04 (s, 1H).

Step B: 2- (5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6 (2-trifluoromethyl-phenyl) -3H-imidazo [4,5-c] Pyridine-4-carbonitrile 4-amino-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridine-2-carbonitrile (described in the previous step) according to the procedure described in Step 25 of Example 25. To 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6 (2-trifluoromethyl-phenyl) -3H-imidazo [4,5 -C] Pyridine-4-carbonitrile was prepared. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.94 to 7.97 (m, 1H), 7.85 to 7.90 (m, 1H), 7.73 to 7.79 (m, 1H) ), 7.66-7.71 (m, 1H), 7.59-7.64 (m, 1H), 4.61 (s, 3H), 1.46 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₂₂ H ₁₈ ClF ₃ N ₆ : 459.1 (M + H), found: 459.2.

  Following the procedures described in Example 32 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 33)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -7-morpholin-4-yl-5- (2-trifluoromethyl-phenyl) -1H-imidazo [ 4,5-b] pyridine (Compound # 61)

Step A: 4-morpholin-4-yl-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine 4-chloro-3-nitro-6- (2-trifluoromethyl-phenyl) ) -Pyridin-2-ylamine (900 mg, 2.83 mmol, prepared as described in Example 1) in DMF (5 mL) was added K ₂ CO ₃ (1.90 g, 14.0 mmol) and then Morpholine (0.240 mL, 2.80 mmol) was added. The resulting mixture was stirred at 80 ° C. overnight. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried (MgSO ₄ ) and concentrated. The resulting residue was purified on silica (0: 100-50: 50 EtOAc / hexanes) to give 4-morpholin-4-yl-3-nitro-6- (2-trifluoromethyl-phenyl)- This gave pyridin-2-ylamine. Mass spectrum (LCMs, ESI pos.) Calculation of mass spectrum (LCMs, ESI pos.) Calculated value of C ₁₆ H ₁₅ F ₃ N ₄ O ₃ : 369.1 (M + H), measured value: 369.1.

Step B: 2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -7-morpholin-4-yl-5- (2-trifluoromethyl-phenyl) -1H -Imidazo [4,5-b] pyridine 2 from 4-morpholin-4-yl-3-nitro-6- (2-trifluoromethyl-phenyl) -pyridin-2-ylamine according to the procedure described in Example 1. -(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -7-morpholin-4-yl-5- (2-trifluoromethyl-phenyl) -1H-imidazo [4 , 5-b] pyridine was prepared. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.76 to 7.81 (m, 1H), 7.59 to 7.66 (m, 1H), 7.51 to 7.58 (m, 2H) 6.57 (s, 1H), 4.27 (s, 3H), 3.98 to 4.05 (m, 4H), 3.90 to 3.97 (m, 4H), 1.45 (s) , 9H) mass spectrum _{(LCMs, APCI pos) C 25} H 26 ClF 3 N 6 O calculated:. 519.3 (M + H) , Found: 519.3.

  Following the procedures described in Example 33 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 34)
2- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -3H-imidazo [4,5-c] pyridine hydrochloride (Compound # 41)

Step A: 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid (2-bromo-5-nitro-pyridin-4-yl) -amide 2-bromo-5-nitro-pyridine-4- A solution of ilamine (62 mg, 0.28 mmol) in THF (5 mL) was treated with NaH (34 mg, 0.85 mmol) under Ar. The resulting solution was stirred for 10 minutes and then treated with a solution of 5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl chloride (62 mg, 0.31 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was directly applied to a silica preparative TLC plate (2000 micrometers) and purified by elution with 3: 7 EtOAc-hexane to give 5-tert-butyl-2-methyl-2H-pyrazole. This gave -3-carboxylic acid (2-bromo-5-nitro-pyridin-4-yl) -amide. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 11.2 (s, 1H), 9.18 (s, 1H), 9.11 (s, 1H), 6.65 (s, 1H). 4.18 (s, 1H), 1.34 (s, 9H).

Step B: 6-Bromo-2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3H-imidazo [4,5-c] pyridine 5-tert-butyl-2-methyl- 2H-pyrazole-3-carboxylic acid (2-bromo-5-nitro-pyridin-4-yl) -amide (79.8 mg, 0.183 mmol, prepared as described in previous step) in acetic acid (1 mL) Was treated with Fe powder (102 mg, 1.82 mmol). The resulting mixture was stirred at 110 ° C. for 1 h, cooled to room temperature, and treated with EtOAc (10 mL) and saturated NaHCO ₃ (10 mL). The organic layer was separated, washed with saturated NaHCO ₃ (10 mL), H ₂ O (10 mL), concentrated, and the resulting residue was dried under reduced pressure to give 6-bromo-2- (5-tert -Butyl-2-methyl-2H-pyrazol-3-yl) -3H-imidazo [4,5-c] pyridine was produced. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 10.0 (br s, 1 H), 8.80 (br s, 1 H), 7.60 (br s, 1 H), 6.60 (m, 1 H) 4.40 (s, 3H), 1.30 (s, 9H).

Step C: 2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -3H-imidazo [4,5-c] pyridine hydrochloride 6- Bromo-2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3H-imidazo [4,5-c] pyridine (50 mg, 0.15 mmol, as described in the previous step. Preparation), a solution of 2-chlorophenylboronic acid (47 mg, 0.30 mmol), 2 M Na ₂ CO ₃ (0.60 mL, 1.2 mmol) and DME (1 mL) was stirred at 90 ° C. for 18 h. The resulting mixture was allowed to cool to room temperature and the organic layer was separated. The organic layer was applied directly to a silica preparative TLC plate (2000 micrometers) and purified by eluting with 3: 7 EtOAc-hexane to give 2- (5-tert-butyl-2-methyl-2H- This yielded pyrazol-3-yl) -6- (2-chloro-phenyl) -3H-imidazo [4,5-c] pyridine.

2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -3H-imidazo [4,5-c] pyridine (22.6 mg, 0. A solution of 061 mmol, prepared as described above) in Et ₂ O (1 mL) was treated with 1 M HCl in Et ₂ O (0.068 mL, 0.068 mmol). The resulting mixture was stirred at room temperature for 10 minutes and concentrated. The residue was dried under reduced pressure to give 2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -3H-imidazo [4,5 -C] gave pyridine hydrochloride. ¹ H-NMR (400 MHz, CD ₃ OD) δ: 9.28 (s, 1H), 8.13 (s, 1H), 7.66-7.71 (m, 2H), 7.63 (td, J = 7.7, 1.8 Hz, 1H), 7.53 to 7.60 (m, 1H), 7.02 (s, 1H), 4.36 (s, 3H), 1.35 (s, 9H). Mass spectrum (LCMs, ESI pos.) Calculated for C ₂₀ H ₂₀ ClN ₅ : 366.1 (M + H), found: 366.2.

  Following the procedures described in Example 34 above, the following representative compounds of the invention were prepared by substituting suitably selected and substituted reagents, starting materials and conditions that would be readily apparent to one skilled in the art.

(Example 35)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] Pyridine (compound # 11)

Step A: Ethyl 3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxylate 5 L 4-neck round bottom flask equipped with overhead air stirrer, positive pressure nitrogen inlet, thermocouple and addition funnel Was charged with a solution of ethyl 3-tert-butyl-1-methyl-1H-pyrazole-5-carboxylate (250 g, 1.19 mol) in dichloromethane (2.5 L). The resulting solution was cooled to 10 ° C. with a wet ice bath. Sulfuryl chloride (149 mL, 1.49 mol) was added via an addition funnel to maintain the temperature at 21-31 ° C. The resulting mixture was then stirred at room temperature for 2 hours. A separate 12 L four neck flask equipped with an overhead air stirrer and thermocouple was charged with H ₂ O (3.75 L) and cooled to 10 ° C. This mixture was then added via an addition funnel while maintaining the temperature below 32 ° C. and the resulting mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 1 L). The organic layer was carefully washed with NaHCO ₃ (saturated, 2 × 2 L), brine (1.25 L), dried over Na ₂ SO ₄ , filtered and evaporated to give ethyl 3-tert- as a white solid. This gave butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxylate. ¹ H NMR (chloroform-d) δ: 4.39 (q, J = 7.1 Hz, 2H), 4.07 (s, 3H), 1.29 to 1.49 (m, 12H).

Step B: 3-tert-Butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxylic acid To a 12 L 4-neck round bottom flask equipped with an overhead air stirrer, positive pressure nitrogen inlet, thermocouple and addition funnel , Ethyl 3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxylate (282 g, 1.15 mol) and EtOH (4.3 L) were charged. 3M NaOH (960 mL, 2.87 mol) was added in one portion and the resulting slurry began to clear immediately. The resulting mixture was stirred at room temperature for 2 hours, resulting in a turbid solution. The turbid solution was evaporated and the resulting aqueous slurry was diluted with H ₂ O ( ₂ L). The basic solution was acidified to pH˜2 using concentrated HCl. The aqueous phase was extracted with dichloromethane (2 × 800 mL), dried over MgSO ₄ , filtered and evaporated to give 3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5 as an off-white solid. -The carboxylic acid was produced. ¹ H NMR (chloroform-d) δ: 4.11 (s, 3H), 1.41 (s, 9H).

Step C: 3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxychloride Magnetic stirrer, positive pressure nitrogen inlet, gas outlet leading to sodium bicarbonate scrubber, thermocouple and addition funnel A 3 L four-necked round bottom flask equipped with tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxylic acid (99.68 g, 0.460 mol), toluene (1.50 L) and dimethylformamide ( 1.78 mL) was charged. Oxalyl chloride (41.50 mL, 60.71 g, 0.469 mol) was added via addition funnel over 15 minutes and the temperature was observed to rise to 23 ° C., degassing being significant but controlled. It was. The resulting mixture was initially turbid but turned clear after 30 minutes. The mixture was concentrated to give 3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxychloride as a yellow solid. ¹ H NMR (400 MHz, chloroform-d) δ 1.40 (s, 9H), 4.04 (s, 3H).

Step D: 6-Chloro-2-methoxy-3-nitropyridin-4-amine A 5 L 4-neck round bottom flask equipped with an overhead stirrer, positive pressure nitrogen inlet, 500 mL addition funnel with nitrogen outlet and thermocouple , 6-Dichloro-3-nitropyridin-4-amine (150.0 g, 0.72 mol) and MeOH (1.50 L) were charged and the resulting brown suspension was stirred at room temperature. NaOCH ₃ (25% MeOH solution, 260 mL, 1.155 mol) was charged to the addition funnel and added over 30 minutes (temperature did not exceed 32 ° C.). The resulting red suspension was stirred for 1 hour, then transferred to a 3 L round bottom flask (with MeOH) and evaporated to near dryness on a rotary evaporator. The resulting red sludge was diluted with aqueous ammonium chloride (1.75 L) and extracted with EtOAc (2 × 900 mL). The combined organics were washed with water (150 mL) and the aqueous layer was diluted with brine (100 mL) and back extracted with EtOAc (100 mL). The combined organics were dried (MgSO ₄ ) and concentrated under reduced pressure at 60 ° C. to give 6-chloro-2-methoxy-3-nitropyridin-4-amine as a yellow solid. ¹ H NMR (chloroform-d) δ: 6.36 (s, 1H), 6.14 (br.s., 2H), 4.04 (s, 3H).

Step E: 6- (2-Chlorophenyl) -2-methoxy-3-nitropyridin-4-amine A 5 L 4-neck round bottom flask equipped with a mechanical stirrer, water condenser with nitrogen inlet, thermocouple and stopper. 6-chloro-2-methoxy-3-nitro-4-pyridinamine (125.30 g, 0.615 mol), 2-chlorophenylboronic acid (116.36 g, 0.744 mol), sodium carbonate (164.97 g, 1 .54 mol), toluene (1.80 L), water (0.8 L) and ethanol (0.625 L) were charged, and the resulting mixture was stirred to obtain a red slurry. The slurry was heated to cause a gentle reflux over 15 minutes to degas the solution and then the temperature was reduced to 60 ° C. The resulting mixture was treated with (1,1′-bis- (di-tert-butylphosphino) ferrocenepalladium (II) chloride (40.8 g, 61 mmol), the temperature was raised to 69 ° C. and gentle reflux The temperature was then reduced to 60 ° C. and stirring was continued for 17 hours The resulting mixture was diluted in water (2 L) and ethyl acetate (1 L) and then filtered through CELITE. The filtrate layers were separated and the aqueous layer was further extracted with ethyl acetate (3 × 500 mL) The combined organics were dried (MgSO ₄ ) and concentrated. A dark oil was produced, which was dissolved in dichloromethane and slurried with silica gel (325 g), which was loaded onto BIOTAGE 150M (2.5 kg silica) Elution with methane (3 L) and ethyl acetate-dichloromethane 1:19 (9 L) Finally, fractions of appropriate purity from heptane (500 mL) were concentrated to yield the title compound as a residue. 282 g) with MTBE (0.50 L), heated in a water bath at 40 ° C. for 30 minutes, transferred to a mechanically stirred 5 L round bottom flask and then diluted with heptane (2 L). Stir at room temperature for 1 hour and collect the solid by filtration.The filter cake was washed with MTBE-heptane (1: 9, 500 mL) and heptane (500 mL) and dried in a vacuum oven at 50 ° C. for 45 minutes. As a result, 6- (2-chlorophenyl) -2-methoxy-3-nitropyridin-4-amine was produced as a yellow solid ¹ H NMR (4 00 MHz, chloroform-d) δ 3.62 (s, 1H), 4.07 (s, 3H), 6.14 (br.s., 2H), 6.69 (s, 1H), 7.30-7 .40 (m, 2H), 7.42-7.52 (m, 1H), 7.59-7.66 (m, 1H).

Step F: 3-tert-butyl-4-chloro-N- (6- (2-chlorophenyl) -2-methoxy-3-nitropyridin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide Into a 5 L 4-neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet, addition funnel with stopper and thermocouple was added 6- (2-chlorophenyl) -2-methoxy-3-nitropyridin-4-amine (111.40 g). 0.398 mol) and tetrahydrofuran (1.90 L). The resulting mixture was cooled to 3 ° C. with an ice-water bath and then treated carefully with sodium hydride (31.85 g, 0.796 mol) in one portion (an exotherm up to 7 ° C. was observed) until the dark red slurry was occured. The slurry was cooled to 1 ° C. and a solution of 3-tert-butyl-1-methyl-1H-pyrazole-4-carbonyl chloride (113.05 g, 0.438 mol) in tetrahydrofuran (0.275 L) was added via an addition funnel. An dropwise exotherm up to 10 ° C. was observed over 30 minutes. The ice bath was drained and the resulting mixture reached 8 ° C. over 30 minutes. The resulting mixture was then poured into saturated ammonium chloride (2.5 L) and extracted with ethyl acetate (2 L, 2 × 1 L). The combined organics were washed with brine (1 L), dried overnight (MgSO ₄ ) and protected from light. Concentration of the organic phase yielded the title compound as a residue. The residue was triturated with heptane (2.25 L) for 30 minutes at 60 ° C. and the resulting mixture was cooled to room temperature while protected from light. The resulting solid was collected by filtration, washed with heptane (250 mL) and dried in a vacuum oven (50 ° C.) for 5 hours to give 3-tert-butyl-4-chloro-N— (6 as a yellow solid. This gave-(2-chlorophenyl) -2-methoxy-3-nitropyridin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide. ¹ H NMR (400 MHz, chloroform-d) δ 1.41 (s, 9H), 4.10 (s, 3H), 4.12 (s, 3H), 7.34-7.43 (m, 2H), 7.47-7.55 (m, 1H), 7.60-7.68 (m, 1H), 8.49 (s, 1H), 10.13 (br.s., 1H).

Step G: N- (3-amino-6- (2-chlorophenyl) -2-methoxypyridin-4-yl) -3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxamide 2 .25L plastic-coated Parr bottles with 3-tert-butyl-4-chloro-N- (6- (2-chlorophenyl) -2-methoxy-3-nitropyridin-4-yl) -1-methyl-1H-pyrazole -5-Carboxamide (55.30 g, 0.115 mol) and ethyl acetate (0.55 L) were charged. To the resulting slurry was added a slurry of 5% Pt (sulfurized) / C (2.80 g) in ethyl acetate (about 20 mL). The resulting mixture was stirred under 241 to 276 kPa (35 to 40 psi) hydrogen and refilled with hydrogen gas as needed. After 3 hours, hydrogen uptake stopped. The resulting mixture was filtered through CELITE to remove the catalyst and the filter cake was washed with ethyl acetate. The filtrate was concentrated to give N- (3-amino-6- (2-chlorophenyl) -2-methoxypyridin-4-yl) -3-tert-butyl-4-chloro-1-methyl-1H- as an off-white solid. This gave pyrazole-5-carboxamide. ¹ H NMR (400 MHz, chloroform-d) δ 1.42 (s, 9H), 3.98 (br.s., 2H), 4.06 (s, 3H), 4.15 (s, 3H), 7 .27-7.35 (m, 2H), 7.44 (dd, J = 7.83, 1.22 Hz, 1H), 7.55 (s, 1H), 7.63 (dd, J = 7. 58, 1.71 Hz, 1H), 8.54 (br.s., 1H).

Step H: 2- (3-tert-butyl-4-chloro-1-methyl-1H-pyrazol-5-yl) -6- (2-chlorophenyl) -4-methoxy-3H-imidazo [4,5-c ] Pyridine A 2 L four-necked round bottom flask equipped with a mechanical stirrer, reflux condenser with nitrogen outlet, positive pressure nitrogen inlet and thermocouple was charged with N- (3-amino-6- (2-chlorophenyl) -2- Methoxypyridin-4-yl) -3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxamide (156.2 g, 0.346 mol) and AcOH (ice, 780 mL) were charged. The resulting mixture was heated to 90 ° C. for 2 hours. The resulting mixture was then cooled to 50 ° C., transferred to a single neck round bottom flask and concentrated on a rotary evaporator (50 ° C. bath). The resulting orange pasty solid was dissolved in EtOAc (1.5 L) and added to a separatory funnel containing saturated aqueous sodium bicarbonate (2 L) and EtOAc (1.5 L). The pH of this aqueous solution was still acidic, but was adjusted to pH 8-9 with 50% wt / wt NaOH (about 10 mL) and then returned to neutrality with aqueous HCl (2M, 120 mL) to a final pH of 6-8. It was. The turbid organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 500 mL). The combined turbid organic layers were warmed with gentle stirring in a 50 ° C. bath for 1-2 minutes resulting in a clear orange solution. The warm organic layer was quickly washed with brine (500 mL), dried (MgSO4) (but optionally warmed through the drying process), filtered and the volatiles removed under reduced pressure. The resulting residue was allowed to crystallize, then redissolved with dichloromethane, resulting in a turbid mixture. The resulting concentrate was loaded onto BIOTAGE 150M (2.5 kg silica pre-wetted with 4 L heptane), heptane (4 L), 10% EtOAc in heptane (12 L) and finally 20% EtOAc. Eluting with a solution of heptane (16 L), whereby fractions of suitable purity were collected and concentrated to give the title compound.

  2- (3-tert-butyl-4-chloro-1-methyl-1H-pyrazol-5-yl) -6- (2-chlorophenyl) -4-methoxy-3H-imidazo [4 with heptane (1.66 L) , 5-c] pyridine (166 g) was used to perform final purification using a 3 L one-neck round bottom flask. The flask was swirled in a rotary evaporator bath at 45-48 ° C. for 15 minutes, scraping the surface of the flask and swirling continued for an additional 15 minutes. Heat was turned off, ice was added to the bath and the contents swirled to room temperature. The solid was collected by filtration, washed with heptane (100 mL) and dried in a vacuum oven (50 ° C.) for 16 hours to give 2- (3-tert-butyl-4-chloro-1-methyl as an off-white solid. -1H-pyrazol-5-yl) -6- (2-chlorophenyl) -4-methoxy-3H-imidazo [4,5-c] pyridine was produced. 1H NMR (chloroform-d) δ: 10.25 (br.s., 1H), 7.75 (dd, J = 7.6, 1.7 Hz, 1H), 7.64 to 7.72 (m, 1H), 7.47-7.54 (m, 2H), 7.28-7.43 (m, 2H), 4.37 (s, 3H), 4.20 (s, 3H), 1.45 (S, 9H). According to NMR, multiple signals for some resonance were observed due to either tautomerization of the imidazole ring or restriction of single bond rotation.

  It was determined by powder X-ray diffraction whether the product prepared as above was in crystalline form. More specifically, a pXRD sample of the off-white product prepared as described above was packed on a zero background holder and scanned under ambient temperature and humidity conditions. This sample was scanned at 2θ of 3 to 35 °, but the step size was 0.0165 ° 2θ and the continuous time was 10.16 seconds. The effective scan speed was 0.2067 ° / s. Instrument voltage and current settings were 45 kV and 40 mA.

  2- (3-tert-butyl-4-chloro-1-methyl-1H-pyrazol-5-yl) -6- (2-chlorophenyl) -4-methoxy-3H-imidazo [4, prepared as above. The crystalline form of 5-c] pyridine was characterized by its powder X-ray diffraction pattern including multiple peaks, listed in Table XRD-1 below.

  Preferably, 2- (3-tert-butyl-4-chloro-1-methyl-1H-pyrazol-5-yl) -6- (2-chlorophenyl) -4-methoxy-3H-imidazo prepared as described above. The crystalline form of [4,5-c] pyridine is characterized by its XRD pattern, including a peak having a relative intensity of about 10% or greater, more preferably a peak having a relative intensity of about 20% or greater.

(Example 36)
2- (5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl) -6- (2-chloro-phenyl) -4-methoxy-3H-imidazo [4,5-c] Pyridine potassium salt (Compound # 11)

In a 50 mL one-necked round bottom flask was added 2- (3-tert-butyl-4-chloro-1-methyl-1H-pyrazol-5-yl) -6- (2-chlorophenyl) -4-methoxy-3H-imidazo [4 , 5-c] pyridine (1.99 g, 4.27 mmol, prepared as described above in Example 35), tetrahydrofuran (4.00 mL) and methanol (4.00 mL) were charged to give a solution. This solution was treated with potassium methoxide (approximately 25% w / w methanol solution, 1.20 mL, 4.28 mmol). The resulting solution was then concentrated to give potassium 2- (3-tert-butyl-4-chloro-1-methyl-1H-pyrazol-5-yl) -6- (2-chlorophenyl)-as a yellow foam. 4-Methoxyimidazo [4,5-c] pyridine-3-id was produced. ¹ H NMR (DMSO-d ₆ ) δ: 7.71 (dd, J = 7.6, 1.7 Hz, 1H), 7.50 (dd, J = 7.9, 1.3 Hz, 1H), 7 .39 (td, J = 7.5, 1.2 Hz, 1H), 7.35 (s, 1H), 7.27 to 7.34 (m, 1H), 4.03 (s, 3H), 3 97 (s, 3H), 1.39 (s, 9H).

Biological Example 1:
In Vitro Canine TRPM8 Functional Assay The functional activity of representative compounds of formula (I) of the present invention is quantified by measuring changes in intracellular calcium concentration using Ca ²⁺ sensitive fluorescent dyes. It was. Changes in fluorescence signal were monitored with a FLIPR ™ (Molecular Devices) or FDSS (Hamamatsu) fluorescence plate reader. An increase in intracellular Ca ²⁺ concentration was detected immediately after activation with icilin.

HEK 293 cells stably expressing canine TRPM8 were minimally added to Dulbecco with 10% FBS, 2 mM L-glutamine, 100 units / mL penicillin, 100 ug / mL streptomycin, and 400 μg / mL G418. It was routinely grown as a monolayer in the essential medium. Cells were maintained at 37 ° C. in 5% CO ₂ . Twenty-four hours prior to assay, cells were seeded at a density of 5,000 cells / well in culture medium in a black-walled clear-bottomed poly-D-lysine-coated 384-well plate (BD Biosciences, NJ, USA). And grown overnight at 37 ° C. with 5% CO ₂ . On the day of the assay, the growth medium was removed and the cells were filled with Calcium 3 Dye (Molecular Devices) with 5% CO ₂ at 37 ° C. for 35 minutes and then incubated at room temperature and room atmosphere for 25 minutes. The cells were then tested for agonist-induced increases in intracellular Ca ²⁺ levels using FLIPR ™ or FDSS. Cells are treated with various concentrations of the compound of formula (I) and intracellular Ca ²⁺ is obtained 5 minutes prior to obtaining a final concentration that yields a maximum response of about 80% by adding icilin to all wells. Was measured. The EC ₅₀ or IC ₅₀ value of the compound of the present invention was determined from an 8-point concentration response test. The concentration of each compound required to elicit or inhibit 50% of the maximum response is noted.

Maximum fluorescence intensity (FI) achieved by the addition of icilin was transferred from FLIPR ™ or FDSS software and further analyzed by GraphPad Prism 3.02 (Graph Pad Software Inc., CA, USA). . Prior to normalizing the data, the base FI was pre-subtracted from the maximum response%. Curves generated using the mean at each data point of quadruplicate wells were analyzed using either sigmoidal dose response or non-linear regression of sigmoidal dose response (variable slope). It was. Finally, EC ₅₀ and IC ₅₀ values were calculated by the optimal curve determined by GraphPad Prism.

  Representative compounds of the present invention were tested according to the procedure as described in Biological Example 1 above, and the results are listed in Table 2 below.

^A Note compounds were prepared and tested as multiple batches, as the free base and / or as different corresponding salt forms. For the above compounds, the biological activity listed in Table 2 above is the average of the measured values.

Biological Example 2:
Inhibition of icilin-induced “severe tremor” in rats Icilin was first developed as an “ultra-cool” compound by Delmar Chemicals Ltd. Subsequently, icilin is one of the most potent known agonists of TRPM8 (MCKEMY, DD, et al “Identification of a cold receptor ageneral roll for TRP channels, 58”). , Vol. 416 (6876), having an EC ₅₀ value of 0.2 μM to stimulate calcium ion influx into TRPM transduced cells (BEHRENDT, HJ, et al., “Characterization of the mouse”. cold menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorome tric imaging plate reader (FLIPR) assay ", Brit J Pharmacol, 2004, pp 737-745, Vol. 141 (4)). Initial in vivo testing of icilin showed that icilin caused a “severe” tremor in the rat. Similar trembling or jumping behavior was also observed in mice, rabbits, cats, dogs and monkeys. In humans, icilin causes a cold sensation upon contact with the mucous membrane, cold drenching occurs when 0.1 mg is dripped onto the tongue, and oral intake of 5-10 mg results in 30-60 minutes of cold in the mouth, pharynx and chest. Caused persistently (WEI, ET, et al., “AG-3-5: a chemical producing senses of cold”, J Pharm Pharmacol., 1983, pp 110-112, Vol. 35). Inhibition of or recovery from icilin-induced tremor behavior in rodents provides evidence of TRPM8 involvement and functional blockade, whereby the disease or condition is affected by modulation of the TRPM8 receptor Provides evidence on the usefulness of TRPM8 antagonists for the treatment or prevention of a disease or condition in a treated mammal.

Male Sprague Dawley rats (220-450 g, Charles River Labs, n = 6-9 / treatment) were used to assess the ability of the test compound icilin-induced “severe” tremor (WDS) inhibition. The test compound was orally administered in a 10% hydroxypropyl-β-cyclodextrin (HP-β-CD) solution 60 minutes before icilin. Next, icilin was administered intraperitoneally at 10 mg saltol / H ₂ O solution at 3.0 mg / kg and spontaneous “severe” tremors were counted over 10 minutes in the 10 minutes following the icilin injection. The results for representative compounds of the invention are shown in Table 3 below as percent tremor inhibition calculated as follows.
Inhibition% = [1− (number of intense tremors due to test compound / number of tremors due to vehicle)] × 100.

Biological Example 3: Chronic constriction (CCI) -induced model of neuropathic pain-acetone-induced hypersensitivity using male Sprague-Dawley rats (225-450 g, n = 5-8 / treatment)) The ability of the test compounds to recover CCI-induced cold sensitivity was evaluated. Bennett et al. (According to BENNETT, GJ, et al., “A peripheral mononeuropathy in rat products products of pain sensation like this in man”, Pain, 1988, pp 87-33). In addition, 4 loose ligatures with 4-0 chronic guts under inhalation anesthesia were surgically placed around the left sciatic nerve. 14 to 35 days after CCI surgery, the test animals were placed in an elevated observation chamber with a wire mesh floor, and acetone was administered 5 times by sprinkling acetone on the plantar surface using a continuous use syringe (approximately 5 minutes). 0.05 mL / dose at intervals). Retracting or lifting the foot rapidly was considered a positive response. The number of positive responses was recorded for each rat over 5 trials. Following baseline withdrawal measurements, test compounds were administered orally in a 10% hydroxypropyl-β-cyclodextrin (HP-β-CD) solution. The number of withdrawals was re-measured 2 hours after compound administration. A representative compound of the invention was administered at 10 mg / kg as a 10% HP-β-CD solution and tested according to this procedure. The results are presented below as percent tremor inhibition calculated for each subject by the following treatment and then averaged.
Inhibition% = [1− (test compound pull-in / pre-test pull-in)] × 100.

  Following the procedures as described in Biological Example 2 and Biological Example 3 above, representative compounds of the present invention were tested and the results are listed in Table 3 below.

Formulation Example 1
Solid Oral Administration Formulation-Predictive Example As a specific embodiment of the oral composition, Compound # 11, 100 mg prepared in Example 28 above, was blended with sufficient fine powdered lactose to give a total amount of 580-590 mg, Fill size O hard gel capsules.

  While the foregoing description, together with examples provided for purposes of illustration, teaches the principles of the invention, its practice is within the scope of the following claims and their equivalents. It should be understood that all possible variations, adaptations and / or modifications are included.

Claims (35)

A compound of formula (I), or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof:
Where
R ¹ is selected from the group consisting of hydrogen, fluoro, chloro, fluorinated C _1-4 alkyl and fluorinated C _1-4 alkoxy;
R ² is selected from the group consisting of hydrogen, chloro, bromo, C _1-4 alkyl, fluorinated C _1-4 alkyl and fluorinated C _1-4 alkoxy, provided that R ² is other than hydrogen.
And
Selected from the group consisting of
In the formula, R ³ is hydrogen, chloro, cyano, C _1-4 alkyl, fluorinated C _1-4 alkyl, C _1-4 alkoxy, fluorinated C _1-4 alkoxy, —O— (CH ₂ ) ₂ —. OH, —O—CH ₂ —CO ₂ H, —O— (CH ₂ ) ₂ —O— (C _1-4 alkyl), —O—CH ₂ — (fluorinated C _1-2 alkyl), —O—. Selected from the group consisting of (CH ₂ ) ₂ —NR ^A R ^B and —NR ^A R ^B ;
Wherein R ^A and R ^B are each independently selected from the group consisting of hydrogen and C _1-4 alkyl;
Alternatively, ^{R A} and ^{R B,} together with the nitrogen atom to which they are bonded, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl - piperidin-1-yl Forming a ring structure selected from the group consisting of 4-methyl-piperazin-1-yl and morpholin-4-yl;
Q is an optionally substituted ring structure selected from the group consisting of rings (a) to (h) and 1-methyl-3-tert-butyl-imidazol-2-yl :
(Wherein, ^{R 5} is _{C 1 to 4} alkyl, ^{R 6} _is selected from the group consisting of _{C 1 to 4} alkyl and fluorinated _{C 1 to 4} alkyl, ^{R 7} is hydrogen, chloro, fluoro, cyano , Selected from the group consisting of C _1-4 alkyl and C _1-4 alkoxy),
Wherein R ⁸ and R ⁹ are each independently selected from the group consisting of C _1-4 alkyl.
Wherein R ¹⁰ is C _1-4 alkyl and R ¹¹ is selected from the group consisting of hydrogen and cyano.
Wherein R ¹² and R ¹³ are each independently selected from the group consisting of hydrogen and C _1-4 alkyl.
Wherein R ¹⁴ is C _1-4 alkyl.
Wherein R ¹⁵ is C _1-4 alkyl and R ¹⁶ is selected from the group consisting of hydrogen, chloro and bromo.
(Wherein R ¹⁷ is C _1-4 alkyl). R ¹ is selected from the group consisting of hydrogen, fluoro, chloro, fluorinated C _1-2 alkyl and fluorinated C _1-2 alkoxy;
R ² is selected from the group consisting of hydrogen, chloro, trifluoromethyl and trifluoromethoxy, provided that R ² is other than hydrogen
And
Selected from the group consisting of
In the formula, R ³ is hydrogen, chloro, cyano, C _1-2 alkyl, fluorinated C _1-2 alkyl, C _1-4 alkoxy, fluorinated C _1-2 alkoxy, —O— (CH ₂ ) ₂ —. OH, —O—CH ₂ —CO ₂ H, —O— (CH ₂ ) ₂ —O— (C _1-4 alkyl), —O—CH ₂ — (fluorinated C _1-2 alkyl), —O—. Selected from the group consisting of (CH ₂ ) ₂ —NR ^A R ^B and —NR ^A R ^B ;
R ^A and R ^B are each independently selected from the group consisting of hydrogen and C _1-2 alkyl, or R ^A and R ^B together with the nitrogen atom to which they are attached, pyrrolidin-1-yl Forming a ring structure selected from the group consisting of: piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;
Q is an optionally substituted ring structure selected from the group consisting of rings (a) to (h) and 1-methyl-3-tert-butyl-imidazol-2-yl :
(Wherein, ^{R 5} is _{C 1 to 4} alkyl, ^{R 6} _is selected from the group consisting of _{C 1 to 4} alkyl and fluorinated _{C 1 to 4} alkyl, ^{R 7} is hydrogen, chloro, fluoro, cyano , Selected from the group consisting of C _1-2 alkyl and C _1-2 alkoxy),
Wherein R ⁸ and R ⁹ are each independently selected from the group consisting of C _1-4 alkyl.
Wherein R ¹⁰ is C _1-4 alkyl and R ¹¹ is selected from the group consisting of hydrogen and cyano.
Wherein R ¹² and R ¹³ are each independently selected from the group consisting of hydrogen and C _1-4 alkyl.
Wherein R ¹⁴ is selected from the group consisting of C _1-4 alkyl.
Wherein R ¹⁵ is C _1-4 alkyl and R ¹⁶ is selected from the group consisting of hydrogen, chloro and bromo.
(Wherein R ¹⁷ is C _1-2 alkyl)
The compound according to claim 1, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. R ¹ is selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl and trifluoromethoxy;
R ² is selected from the group consisting of hydrogen and chloro, provided that when R ² is chloro
And
Selected from the group consisting of
R ³ is hydrogen, chloro, cyano, C _1-2 alkyl, trifluoromethyl, C _1-4 alkoxy, —O— (CH ₂ ) ₂ —OH, —O—CH ₂ —CO ₂ H, —O—. _{(CH 2) 2 -O- (C} 1~2 _{alkyl), - O-CH 2 -} ( fluorinated _{C 1 to 2 alkyl), - O- (CH 2)} 2 -NR A R B, pyrrolidin-1 Selected from the group consisting of yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;
R ^A and R ^B are each independently selected from C _1-2 alkyl, or R ^A and R ^B together with the nitrogen atom to which they are attached, pyrrolidin-1-yl, piperidin-1- Forming a ring structure selected from the group consisting of yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;
Q is an optionally substituted ring structure selected from the group consisting of rings (a) to (h) and 1-methyl-3-tert-butyl-imidazol-2-yl :
(Wherein, ^{R 5} is _{C 1 to 4} alkyl, ^{R 6} _is selected from the group consisting of _{C 1 to 4} alkyl and fluorinated _{C 1 to 4} alkyl, ^{R 7} is hydrogen, chloro, fluoro, cyano , Selected from the group consisting of C _1-2 alkyl and C _1-2 alkoxy),
Wherein R ⁸ and R ⁹ are each independently selected from the group consisting of C _1-4 alkyl.
Wherein R ¹⁰ is C _1-4 alkyl and R ¹¹ is selected from the group consisting of hydrogen and cyano.
Wherein R ¹² is hydrogen and R ¹³ is selected from the group consisting of C _1-4 alkyl.
Wherein R ¹⁴ is selected from the group consisting of C _1-4 alkyl.
In which R ¹⁵ is C _1-4 alkyl and R ¹⁶ is selected from the group consisting of hydrogen and bromo; and
Wherein R ¹⁷ is C _1-2 alkyl.
The compound according to claim 2, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. R ¹ is selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl and trifluoromethoxy;
R ² is selected from the group consisting of hydrogen and chloro, provided that when R ² is chloro
And
Selected from the group consisting of
Q is 1-methyl-3-tert-butyl-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4 -Fluoro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazol-5-yl, 1-methyl-3-trifluoromethyl-4-chloro-pyrazol-5-yl, 1 -Methyl-3-tert-butyl-4-methoxy-pyrazol-5-yl, 1-methyl-3- (1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl, 1 -Tert-butyl-pyrazol-4-yl, 1-tert-butyl-5-methyl-pyrazol-4-yl, 1-methyl-3-tert-butyl-imidazol-2-yl, 3-t rt-butyl-isoxazol-5-yl, 3-tert-butyl-4-cyano-isoxazol-5-yl, 4-isopropyl-thien-2-yl, 5-isopropyl-thien-3-yl, 4- tert-butyl-fur-2-yl, 4-tert-butyl-5-bromo-fur-2-yl and
Selected from the group consisting of
4. A compound according to claim 3, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. R ¹ is selected from the group consisting of chloro, fluoro, trifluoromethyl and trifluoromethoxy;
R ² is selected from the group consisting of hydrogen and chloro, provided that when R ² is chloro
And
Selected from the group consisting of
Q is 1-methyl-3-tert-butyl-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4 -Fluoro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-methoxy-pyrazol-5-yl, 1 -Methyl-3- (1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl, 3-tert-butyl-isoxazol-5-yl, 3-tert-butyl-4- Cyano-isoxazol-5-yl, 4-isopropyl-thien-2-yl, 5-isopropyl-thien-3-yl, 4-tert-butyl-fur-2-yl, 4-tert Butyl-5-bromo - fur-2-yl and
Selected from the group consisting of
5. A compound according to claim 4, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. R ¹ is selected from the group consisting of chloro, fluoro, trifluoromethyl and trifluoromethoxy;
R ² is selected from the group consisting of hydrogen and chloro, provided that when R ² is chloro
And
Selected from the group consisting of
Q is 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazol-5-yl, 1-methyl-3- ( 1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl, 3-tert-butyl-isoxazol-5-yl and
Selected from the group consisting of
5. A compound according to claim 4, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. R ¹ is selected from the group consisting of chloro, fluoro, trifluoromethyl and trifluoromethoxy;
R ² is hydrogen;
Selected from the group consisting of
Q is 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazol-5-yl and 1-methyl-3- ( Selected from the group consisting of 1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl,
5. A compound according to claim 4, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. R ¹ is selected from the group consisting of chloro and trifluoromethyl;
R ² is hydrogen;
Selected from the group consisting of
Q is selected from the group consisting of 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl and 1-methyl-3-tert-butyl-4-cyano-pyrazol-5-yl;
5. A compound according to claim 4, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. R ¹ is chloro, R ² is hydrogen,
And Q is 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, or a solvate, hydrate or tautomer thereof. Or a pharmaceutically acceptable salt.   9. A compound according to claim 8, wherein the pharmaceutically acceptable salt is selected from the group consisting of sodium salt, potassium salt and methanesulfonate.   A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1.   A method for producing a pharmaceutical composition comprising the step of mixing the compound according to claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition for use in the treatment of inflammatory pain or neuropathic pain, a therapeutically effective comprising the compound of claim 1 in an amount, pharmaceutical compositions for use in the treatment of inflammatory pain or neuropathic pain Thing . The inflammatory pain is inflammatory bowel disease, visceral pain, migraine, postoperative pain, osteoarthritis, rheumatoid arthritis, back pain, back pain, joint pain, abdominal pain, chest pain, labor pain, musculoskeletal disease, skin disease , Toothache, fever, burn, sunburn, snake bite, poisonous snake bite, spider bite, insect bite, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis / irritability, pruritus, eczema, Due to sore throat, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, pain syndrome after mastectomy, menstrual pain, endometriosis, headache due to sinusitis, tension headache, or arachnoiditis, The pharmaceutical composition according to claim 13. 14. The pharmaceutical composition according to claim 13, wherein the inflammatory pain is inflammatory hyperalgesia. 16. The pharmaceutical composition according to claim 15, wherein the inflammatory hyperalgesia is inflammatory body hyperalgesia or inflammatory visceral hyperalgesia. The inflammatory hyperalgesia is inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal disease, skin disease, postoperative pain, headache, fibromyalgia, toothache, burns, sunburn, insect Bite, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis / irritability, pruritus, eczema, pharyngitis, enteritis, irritability The pharmaceutical composition according to claim 15, which results from bowel syndrome, Crohn's disease, or ulcerative colitis. The pharmaceutical composition according to claim 13, wherein the inflammatory pain is visceral pain. The neuropathic pain is cancer, neurological disease, spinal cord or peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), spinal cord injury, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, neuralgia, lupus, sarcoidosis , Peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathy associated with spinal cord injury, stroke, ALS, Parkinson's disease, multiple sclerosis, sciatica, glossopharyngeal neuralgia, peripheral nerve Inflammation, polyneuritis, stump pain, phantom limb pain, fracture, oral neuropathic pain, Charcot pain, complex local pain syndrome I and II (CRPSI / II), radiculopathy, Guillain-Barre syndrome, perception Abnormal femoral neuralgia, intraoral burning syndrome, optic neuritis, post-fever neuritis, migratory neuritis, segmental neuritis, Gombault neuritis, neuronitis, cervical neuralgia, head neuralgia Knee ganglion neuralgia, glossopharyngial neuralgia, cluster headache, idiopathic neuralgia, intercostal neuralgia, breast neuralgia, Morton neuralgia, nasopharyngeal neuralgia, occipital neuralgia, erythema neuralgia, thruder neuralgia, splenopalatine neuralgia 14. The pharmaceutical composition according to claim 13, caused by supraorbital neuralgia, vulvar pain or paroxysmal neuralgia. The pharmaceutical composition according to claim 19, wherein the neuralgia is trigeminal neuralgia, glossopharyngeal neuralgia, postherpetic neuralgia, or burning pain. The pharmaceutical composition according to claim 13, wherein the neuropathic pain is neuropathic cold allodynia. The neuropathic cold allodynia is spinal and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, burning pain, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral The pharmaceutical composition according to claim 21, which is pain caused by neuritis, polyneuritis, complex regional pain syndrome I and II (CRPSI / II), or radiculopathy. A pharmaceutical composition for use in the treatment of cardiovascular disease exacerbated by cold selected from peripheral vascular disease, vascular hypertension, pulmonary hypertension, Raynaud's disease, and coronary artery disease, wherein the therapeutically effective amount. A pharmaceutical composition comprising the compound described in 1.   Drugs for treating (a) inflammatory pain, (b) neuropathic pain, (c) cardiovascular disease exacerbated by cold, or (d) lung disease exacerbated by cold in a patient in need of treatment Use of a compound according to claim 1 in the preparation of A compound of formula (IB) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof:
Where
R ¹ is selected from the group consisting of hydrogen, fluoro, chloro, fluorinated C _1-4 alkyl and fluorinated C _1-4 alkoxy;
R ² is selected from the group consisting of hydrogen, chloro, bromo, C _1-4 alkyl, fluorinated C _1-4 alkyl and fluorinated C _1-4 alkoxy;
R ³ is hydrogen, chloro, cyano, C _1-4 alkyl, fluorinated C _1-4 alkyl, C _1-4 alkoxy, fluorinated C _1-4 alkoxy, —O— (CH ₂ ) ₂ —OH, — O—CH ₂ —CO ₂ H, —O— (CH ₂ ) ₂ —O— (C _1-4 alkyl), —O—CH ₂ — (fluorinated C _1-2 alkyl), —O— (CH ₂ ) Selected from the group consisting of _2- NR ^A R ^B and —NR ^A R ^B ;
R ^A and R ^B are each independently selected from the group consisting of hydrogen and C _1-4 alkyl, or R ^A and R ^B together with the nitrogen atom to which they are attached, pyrrolidin-1-yl Forming a ring structure selected from the group consisting of: piperidin-1-yl, piperazin-1-yl, 4-methyl-piperidin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl ,
Q is an optionally substituted ring structure selected from the group consisting of rings (a)-(h):
(Wherein, ^{R 5} is _{C 1 to 4} alkyl, ^{R 6} _is selected from the group consisting of _{C 1 to 4} alkyl and fluorinated _{C 1 to 4} alkyl, ^{R 7} is hydrogen, chloro, fluoro, cyano , Selected from the group consisting of C _1-4 alkyl and C _1-4 alkoxy),
Wherein R ⁸ and R ⁹ are each independently selected from the group consisting of C _1-4 alkyl.
Wherein R ¹⁰ is C _1-4 alkyl and R ¹¹ is selected from the group consisting of hydrogen and cyano.
Wherein R ¹² and R ¹³ are each independently selected from the group consisting of hydrogen and C _1-4 alkyl.
Wherein R ¹⁴ is C _1-4 alkyl.
Wherein R ¹⁵ is C _1-4 alkyl and R ¹⁶ is selected from the group consisting of hydrogen, chloro and bromo.
(Wherein R ¹⁷ is C _1-4 alkyl). R ¹ is selected from the group consisting of hydrogen, fluoro, chloro, fluorinated C _1-2 alkyl and fluorinated C _1-2 alkoxy;
R ² is selected from the group consisting of hydrogen, chloro, trifluoromethyl and trifluoromethoxy;
R ³ is hydrogen, chloro, cyano, C _1-2 alkyl, fluorinated C _1-2 alkyl, C _1-4 alkoxy, fluorinated C _1-2 alkoxy, —O— (CH ₂ ) ₂ —OH, — O—CH ₂ —CO ₂ H, —O— (CH ₂ ) ₂ —O— (C _1-4 alkyl), —O—CH ₂ — (fluorinated C _1-2 alkyl), —O— (CH ₂ ) Selected from the group consisting of _2- NR ^A R ^B and —NR ^A R ^B ;
R ^A and R ^B are each independently selected from C _1-2 alkyl, or R ^A and R ^B together with the nitrogen atom to which they are attached, pyrrolidin-1-yl, piperidin-1- Forming a ring structure selected from the group consisting of yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;
Q is an optionally substituted ring structure selected from the group consisting of rings (a)-(h):
(Wherein, ^{R 5} is _{C 1 to 4} alkyl, ^{R 6} _is selected from the group consisting of _{C 1 to 4} alkyl and fluorinated _{C 1 to 4} alkyl, ^{R 7} is hydrogen, chloro, fluoro, cyano , Selected from the group consisting of C _1-2 alkyl and C _1-2 alkoxy),
Wherein R ⁸ and R ⁹ are each independently selected from the group consisting of C _1-4 alkyl.
Wherein R ¹⁰ is C _1-4 alkyl and R ¹¹ is selected from the group consisting of hydrogen and cyano.
Wherein R ¹² and R ¹³ are each independently selected from the group consisting of hydrogen and C _1-4 alkyl.
Wherein R ¹⁴ is selected from the group consisting of C _1-4 alkyl.
Wherein R ¹⁵ is C _1-4 alkyl and R ¹⁶ is selected from the group consisting of hydrogen, chloro and bromo.
Wherein R ¹⁷ is C _1-2 alkyl.
26. A compound according to claim 25, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. R ¹ is selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl and trifluoromethoxy;
R ² is selected from the group consisting of hydrogen and chloro;
R ³ is hydrogen, chloro, cyano, C _1-4 alkoxy, —O— (CH ₂ ) ₂ —OH, —O—CH ₂ —CO ₂ H, —O— (CH ₂ ) ₂ —O— (C _{1-2 alkyl), - O-CH 2 -} ( fluorinated _{C 1-2 alkyl), - O- (CH 2)} 2 -NR A R B, pyrrolidin-1-yl, piperidin-1-yl, piperazine - Selected from the group consisting of 1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;
R ^A and R ^B are each independently selected from C _1-2 alkyl, or R ^A and R ^B together with the nitrogen atom to which they are attached, pyrrolidin-1-yl, piperidin-1- Forming a ring structure selected from the group consisting of yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;
Q is an optionally substituted ring structure selected from the group consisting of rings (a)-(h):
(Wherein, ^{R 5} is _{C 1 to 4} alkyl, ^{R 6} _is selected from the group consisting of _{C 1 to 4} alkyl and fluorinated _{C 1 to 4} alkyl, ^{R 7} is hydrogen, chloro, fluoro, cyano , Selected from the group consisting of C _1-2 alkyl and C _1-2 alkoxy),
Wherein R ⁸ and R ⁹ are each independently selected from the group consisting of C _1-4 alkyl.
Wherein R ¹⁰ is C _1-4 alkyl and R ¹¹ is selected from the group consisting of hydrogen and cyano.
Wherein R ¹² is hydrogen and R ¹³ is selected from the group consisting of C _1-4 alkyl.
Wherein R ¹⁴ is selected from the group consisting of C _1-4 alkyl.
In which R ¹⁵ is C _1-4 alkyl and R ¹⁶ is selected from the group consisting of hydrogen and bromo; and
Wherein R ¹⁷ is C _1-2 alkyl.
27. A compound according to claim 26, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. R ¹ is selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl and trifluoromethoxy;
R ² is selected from the group consisting of hydrogen and chloro;
R ³ is hydrogen, chloro, cyano, methoxy, ethoxy, isopropoxy, —O—CH ₂ —CF ₃ , —O— (CH ₂ ) ₂ —OCH ₃ , —O— (CH ₂ ) ₂ —OH, — _{O- (CH 2) 2 -CO 2} H, pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, 4-methyl - Piperiajin-1-yl (4-methyl-piperiazin-1 -yl) _{, -O- (CH 2) 2 -N} (CH 3) 2, -O- (CH 2) 2 - ( _{morpholin-4-yl), - O- (CH 2)} 2 - ( pyrrolidin-l-yl) And —O— (CH ₂ ) ₂ — (4-methyl-piperazin-1-yl)
Q is 1-methyl-3-tert-butyl-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4 -Fluoro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazol-5-yl, 1-methyl-3-trifluoromethyl-4-chloro-pyrazol-5-yl, 1 -Methyl-3-tert-butyl-4-methoxy-pyrazol-5-yl, 1-methyl-3- (1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl, 1 -Tert-butyl-pyrazol-4-yl, 1-tert-butyl-5-methyl-pyrazol-4-yl, 1-methyl-3-tert-butyl-imidazol-2-yl, 3-t rt-butyl-isoxazol-5-yl, 3-tert-butyl-4-cyano-isoxazol-5-yl, 4-isopropyl-thien-2-yl, 5-isopropyl-thien-3-yl, 4- tert-butyl-fur-2-yl, 4-tert-butyl-5-bromo-fur-2-yl and
Selected from the group consisting of
28. A compound according to claim 27, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. R ¹ is selected from the group consisting of chloro, fluoro, trifluoromethyl and trifluoromethoxy;
R ² is selected from the group consisting of hydrogen and chloro;
R ³ is hydrogen, chloro, cyano, methoxy, isopropoxy, —O—CH ₂ —CF ₃ , —O— (CH ₂ ) ₂ —OCH ₃ , —O— (CH ₂ ) ₂ —OH, pyrrolidine-1 - yl, morpholin-4-yl, piperidin-1-yl, 4-methyl - _{Piperiajin-1-yl, -O- (CH 2) 2 -N} (CH 3) 2 and -O- _{(CH 2) 2} - Selected from the group consisting of (morpholin-4-yl)
Q is 1-methyl-3-tert-butyl-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4 -Fluoro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-methoxy-pyrazol-5-yl, 1 -Methyl-3- (1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl, 3-tert-butyl-isoxazol-5-yl, 3-tert-butyl-4- Cyano-isoxazol-5-yl, 4-isopropyl-thien-2-yl, 5-isopropyl-thien-3-yl, 4-tert-butyl-fur-2-yl, 4-tert Butyl-5-bromo - fur-2-yl and
Selected from the group consisting of
29. A compound according to claim 28, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. R ¹ is selected from the group consisting of chloro, trifluoromethyl and trifluoromethoxy;
R ² is selected from the group consisting of hydrogen and chloro;
R ³ is chloro, cyano, methoxy, isopropoxy, —O—CH ₂ —CF ₃ , —O— (CH ₂ ) ₂ —OCH ₃ , —O— (CH ₂ ) ₂ —OH, pyrrolidin-1-yl. , morpholin-4-yl, piperidin-1-yl, 4-methyl - Piperiajin-1-yl and -O- _{(CH 2) 2} - is selected from the group consisting of (morpholin-4-yl),
Q is 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazol-5-yl, 1-methyl-3- ( 1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl, 3-tert-butyl-isoxazol-5-yl and
Selected from the group consisting of
29. A compound according to claim 28, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. R ¹ is selected from the group consisting of chloro, fluoro, trifluoromethyl and trifluoromethoxy;
R ² is hydrogen;
R ³ is chloro, methoxy, isopropoxy, —O—CH ₂ —CF ₃ , —O— (CH ₂ ) ₂ —OCH ₃ , —O— (CH ₂ ) ₂ —OH, morpholin-4-yl, piperidine 1-yl, and -O- _{(CH 2) 2} - is selected from the group consisting of (morpholin-4-yl),
Q is 1-methyl-3-tert-butyl-4-chloro-pyrazol-5-yl, 1-methyl-3-tert-butyl-4-cyano-pyrazol-5-yl and 1-methyl-3- ( Selected from the group consisting of 1,1-dimethyl-2-fluoro-ethyl) -4-chloro-pyrazol-5-yl,
29. A compound according to claim 28, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. R ¹ is selected from the group consisting of chloro and trifluoromethyl, R ² is hydrogen, R ³ is —OCH ₃ , Q is 1-methyl-3-tert-butyl-4-chloro-pyrazole-5 Selected from the group consisting of -yl and 1-methyl-3-tert-butyl-4-cyano-pyrazol-5-yl;
5. A compound according to claim 4, or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. Formula (IS)
Or a pharmaceutically acceptable salt thereof. A crystalline form of a compound of formula (IS), comprising:
Crystalline form including the following pXRD peaks:
Compound of formula (IS)
Or a method of preparing a pharmaceutically acceptable salt thereof, the method comprising:
(A) in the presence of (1,1′-bis- (di-tert-butylphosphino) ferrocenepalladium (II)), in the presence of sodium carbonate in a mixture of water, toluene and ethanol, Reacting 2-methoxy-3-nitro-4-pyridinamine with 2-chlorophenylboronic acid to yield 6- (2-chlorophenyl) -2-methoxy-3-nitropyridin-4-amine;
(B) The above 6- (2-chlorophenyl) -2-methoxy-3-nitropyridin-4-amine is converted into 3-tert-butyl-1-methyl-1H-pyrazole- in tetrahydrofuran in the presence of sodium hydride. Reaction with 4-carbonyl chloride yields 3-tert-butyl-4-chloro-N- (6- (2-chlorophenyl) -2-methoxy-3-nitropyridin-4-yl) -1-methyl-1H- Producing pyrazole-5-carboxamide;
(C) 3-tert-butyl-4-chloro-N- (6- (2-chlorophenyl) -2-methoxy-3-nitropyridine-4 in ethyl acetate in the presence of Pt (sulfurized) / C -Yl) -1-methyl-1H-pyrazole-5-carboxamide is reacted with hydrogen to give N- (3-amino-6- (2-chlorophenyl) -2-methoxypyridin-4-yl) -3-tert Producing -butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxamide;
(D) N- (3-amino-6- (2-chlorophenyl) -2-methoxypyridin-4-yl) -3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxamide Reacting with glacial acetic acid to produce the compound of formula (IS).